Pyrazolonaphthyridine derivatives

ABSTRACT

The target is to provide PDE IV inhibitors which have a highly potent anti-asthmatic and/or COPD-prophylactic/therapeutic profile with unexpectedly excellent safety. A compound of the formula (1): 
     
       
         
         
             
             
         
       
     
     wherein A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may be unsubstituted or optionally substituted with one or more members selected from the group consisting of hydroxyl, halogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl, lower alkoxy-carbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-lower alkylene, lower alkylsulfonyl, lower alkylsulfonyl-amino, and ureido; R 1  is a group selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and lower alkoxycarbonyl; R 2  is hydrogen or lower alkyl; and m is an integer of 1 to 3; or a pharmaceutically acceptable salt thereof, possesses highly excellent PDE IV-specific inhibitory actions and is useful as an anti-asthmatic drug and/or a prophylactic/therapeutic drug for COPD with high safety.

FIELD OF THE INVENTION

The present invention relates to novel condensed naphthyridinederivatives that inhibit phosphodiesterase (hereinafter, referred to as“PDE”) IV, or pharmaceutically acceptable salts thereof, and topharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION

PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) andintracellular cyclic GMP (cGMP) and widely distributed in vivo invarious tissues and organs. Up to now, it has been known that PDEs areclassified into 7 isoenzyme families, i.e., type I to VII PDEs (PDE I toVII), according to their properties. Among them, PDE IV is known to bean enzyme which is predominantly present in airway smooth muscle cellsand a wide variety of inflammatory cells, i.e., neutrophils,eosinophils, lymphocytes, etc. and selectively breaks down cAMP.

In addition, it has been known that an elevation of cAMP levels inairway smooth muscle cells leads to relaxation of the airway smoothmuscles. An increase of cAMP levels in inflammatory cells has also beenknown to suppress an activation of inflammatory cells, including, forexample, a release of cytotoxic proteins from eosinophils, etc.

Therefore, if PDE IV predominantly located in airway smooth muscle cellsand inflammatory cells is inhibited by inhibitors selective for saidisozyme form, an elevation of cAMP levels would be induced in suchcells. As a result, it would be expected to elicit bronchodilatoractions via relaxing airway smooth muscles and anti-inflammatory actionsthrough suppressing inflammatory cell activation. As seen, for example,in Barnette, PROGRESS IN DRUG RESEARCH, USA, Vol. 53, pp. 193-229 (1999)(non-patent document No. 1), such selective inhibitors of PDE IV wouldbe expected to become excellent anti-asthmatic agents and therapeuticagents for chronic obstructive pulmonary disease (COPD).

Up to now, it has been known that theophylline which is a xanthinederivative, rolipram, which is a catechol derivative, etc., areinhibitors of PDE IV. Theophylline inhibits PDE in various tissues dueto its non-selectivity for individual isozymes, thereby exerting notonly a bronchodilator activity to be targeted but also extra actions onheart, CNS, etc. Although rolipram is observed to be selective for PDEIV, it is easily transferred into the CNS due to its property of beingabsorbed. Therefore, rolipram has a drawback that it induces adversecentral side-effects such as an emetic action.

Over the past decade, many pharmaceutical companies have focused on theinhibition of PDE IV for the treatment of asthma. The biological studieson the PDE IV isozyme and the structure-activity relationship of saidinhibitors have recently been reviewed in the literature. In suchprocesses, it has been pointed out that in general the therapeuticutility of selective PDE IV inhibitors, such as the prototypical agentrolipram, have been hampered by nausea and emesis limiting theirtherapeutic potential (J. Med. Chem., 41: 2268 to 2277 (1998):non-patent document No. 2).

It recently becomes known that PDE IV inhibitors produce inhibition ofdrug-metabolizing enzymes such as CYP2D6 and CYP3A4, thereby raising avariety of adverse side-actions. Therefore, there is still a desire todevelop a PDE IV inhibitor free of affecting the drug-metabolizingenzymes.

Under these circumstances, in order to find out pharmaceutical drugshaving an excellent anti-asthmatic efficacy and/or a prophylactic ortherapeutic efficacy on COPD via minimizing undesirable side-effects intissues and organs other than bronchial smooth muscles and inflammatorycells, various PDE IV inhibitors have been screened and examined.

For instance, with an aim at such inhibitors with improved selectivityfor PDE IV, various compounds have been proposed including naphthalenederivatives (e.g., Patent document No. 1: JP, A, 10-226647 (1998)),catechol diethers derivatives (e.g., Patent document No. 2: JP, A,2001-527508), 2,3-di-substituted pyridine derivatives (e.g., Patentdocument No. 3: JP, A, 2001-354655), etc. Further, for the purpose ofdeveloping not only anti-asthmatic agents but also pharmaceutical agentsfor preventing and treating a wide range for diseases, PDE IV-inhibitorycompounds having a naphthyridine ring have been proposed (for example,Patent document No. 4: JP, A, 7-10875 (1995); Patent document No. 5: WO,A, 96/06843; Patent document No. 6: JP, A, 11-106385 (1999); Patentdocument No. 7: JP, A, 2002-138089; Patent document No. 8: WO, A,99/02527; Patent document No. 9; WO, A, 99/38867; Patent document No.10; WO, A, 01/42244; etc.).

Whereas, in connection with compounds where a heterocyclic ring iscondensed to a naphthyridine ring are disclosed compounds havinganti-inflammatory, immunoregulatory, analgesic, and antipyretic actions(for example, Patent document No. 11: JP, A, 5-132484 (1993), Patentdocument No. 12: JP, A, 6-100561 (1994)) and compounds havinganti-inflammatory, immunoregulatory, bronchodilator, and hair-growingactions (for example, Patent document No. 13: JP, A, 5-194515 (1993),Patent document No. 14: JP, B2, 3016905); however, no inhibitory actionon PDE IV is indicated in these prior art compounds.

[Patent document No. 1] JP, A, 10-226647 (1998)[Patent document No. 2] JP, A, 2001-527508[Patent document No. 3] JP, A, 2001-354655[Patent document No. 4] JP, A, 7-10875 (1995)[Patent document No. 5] WO, A, 96/06843[Patent document No. 6] JP, A, 11-106385 (1999)[Patent document No. 7] JP, A, 2002-138089[Patent document No. 8] WO, A, 99/02527[Patent document No. 9] WO, A, 99/38867[Patent document No. 10] WO, A, 01/42244[Patent document No. 11] JP, A, 5-132484 (1993)[Patent document No. 12] JP, A, 6-100561 (1994)[Patent document No. 13] JP, A, 5-194515 (1993)[Patent document No. 14] JP, B2, 3016905[Non-patent document No. 1] PROGRESS IN DRUG RESEARCH, (USA), 53, pp.193-229 (1999)[Non-patent document No. 2] JOURNAL OF MEDICINAL CHEMISTRY, (USA), 41,pp. 2268-2277 (1999)

SUMMARY OF THE INVENTION

The aforementioned compound groups are still unsatisfactory in view ofsolving the problems, i.e., of minimizing unfavorable side effects inother tissues/organs than airway smooth muscle cells and inflammatorycells, in order to develop and provide drugs with excellentanti-asthmatic and/or COPD-preventing/treating profiles.

There is a great desire to find an advantageously safe drug having notonly a highly specific-inhibitory action on PDE IV but also an excellentanti-asthmatic and/or COPD-preventing/treating action.

The present inventors have conducted an extensive research on variouscompounds in order to solve the above problems. As a result, the presentinventors have succeeded in producing uniquepyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives which are derivedfrom the compound having a naphthyridine skeleton (disclosed in WO, A,01/42244) by condensing a imidazole ring to a specific site of thenaphthyridine ring thereof and finding that these novelpyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives are not onlypharmacologically advantageous over the conventional PDE IV inhibitors,but also qualified as excellently safer drugs than the conventional PDEIV inhibitors because it is perceivable that there is a great differencebetween their pharmacologically-effective dose and their effective dosefor inhibiting drug-metabolizing enzymes. Thus, the present inventorshave succeeded in accomplishing this invention.

The present invention, as described herein below, encompasses1-unsubstituted or optionally 1-substitutedpyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives having anunsubstituted or optionally substituted phenyl, pyridyl, 1-oxypyridyl orthienyl group via 1 to 3 methylene chains on the 3 position of thepyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one nucleus.

The present invention provides the following:

1) A compound of the formula (1):

wherein:

A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may beunsubstituted or optionally substituted with one or more membersselected from the group consisting of hydroxyl, halogen, cyano, nitro,lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl,lower alkoxycarbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-loweralkylene, lower alkylsulfonyl, lower alkylsulfonylamino, and ureido;

R¹ is a group selected from the group consisting of hydrogen, hydroxyl,halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and loweralkoxycarbonyl;

R² is hydrogen or lower alkyl; and

m is an integer of 1 to 3;

or a pharmaceutically acceptable salt thereof.

2) The compound according to the above 1), wherein A is phenyl; or apharmaceutically acceptable salt thereof.

3) The compound according to the above 1), wherein A is pyridyl or1-oxypyridyl; or a pharmaceutically acceptable salt thereof.

4) A compound, or a pharmaceutically acceptable salt thereof, which isselected from the group consisting of

-   3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,-   5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,-   5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,-   3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,-   3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,-   3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,    and-   3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one.

5) A pharmaceutical composition which comprises an effective amount of acompound according to any of the above 1) to 4) or a pharmaceuticallyacceptable salt thereof in admixture with a pharmaceutically acceptablecarrier.

6) A phosphodiesterase IV inhibitor comprising an effective amount of acompound according to any of the above 1) to 4) or a pharmaceuticallyacceptable salt thereof.

7) A drug for the prophylaxis and/or treatment of at least one memberselected from diseases or abnormal conditions directly or indirectlyrelated to phosphodiesterase IV, said drug comprising an effectiveamount of a compound according to any of the above 1) to 4) or apharmaceutically acceptable salt thereof.

8.) A drug comprising an effective amount of a compound according to anyof the above 1) to 4) or a pharmaceutically acceptable salt thereof,

said drug for preventing and/or treating at least one respiratorydisease selected from the group consisting of:

-   -   bronchial asthma including chronic bronchial asthma and atopic        asthma; acute bronchitis; chronic bronchitis; asthmatic        bronchitis; pneumonic diseases; pulmonary emphysema; chronic        obstructive pulmonary disease (COPD); and acute respiratory        distress syndrome (ARDS).

9) An anti-asthmatic comprising an effective amount of a compoundaccording to any of the above 1) to 4) or a pharmaceutically acceptablesalt thereof.

The aforementioned diseases or abnormal conditions directly orindirectly related to phosphodiesterase IV may include, for example, thefollowing:

(1) inflammatory diseases, including atopic dermatitis, conjunctivitis,urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation,rhinitis, iridocyclitis, gingivitis, periodontitis, dentoalveolitis,gastritis, ulcerative colitis, Crohn's disease, gastrointestinal ulcer,esophagitis, myositis, encephalitis, myasthenia gravis, multiplesclerosis, neuritis, hepatitis, scar tissue formation, nephritis(including proliferative nephritis), peritonitis, pleurisy, scleritis,scleroderma, scalds or burns, and the like;

(2) systemic or local joint diseases, including osteoarthritis, goutyarthritis, rheumatoid arthritis, malignant rheumatism, psoriaticarthritis, and the like;

(3) inflammatory conditions associated with organ transplantation, etc.,including reperfusion injury, graft versus-host reaction, and the like;

(4) diseases related to urination, including diabetes insipidus,urethritis, urinary incontinence, cystitis, irritable bladder,neurogenic bladder, uremia, uriniferous tubular disorder, pollakiuria,ischuria, and the like;

(5) diseases or abnormal conditions related to tumor necrosis factor(TNF) (for example, TNF-α, etc.) and other cytokines (for example, IL-1,IL-4, IL-6, etc.), including psoriasis, rheumatoid arthritis, ulcerativecolitis, Crohn's disease, septicemia, septic shock, endotoxic shock,gram negative bacillus sepsis, toxic shock syndrome, nephritis,hepatitis, infection (induced by bacteria and viruses), circulatoryfailure (heart failure, arteriosclerosis, myocardial infarction,cerebral apoplexy), and the like;

(6) proliferative diseases, including malignant tumors, leukemia,proliferative dermal diseases (keratosis and various types ofdermatitides), connective tissue diseases and the like;

(7) diseases related to nervous function abnormality, including impairedlearning, memory and recognition related to neurodegenerative disorderssuch as Alzheimer's disease and Parkinson's disease, multiple lateralsclerosis, senile dementia, amyotrophic lateral sclerosis, acutedemyelinating neuritis, muscular dystrophy, and the like;

(8) diseases related to abnormality of mental functions, includingmanic-depressive psychosis, schizoid, anxiety, panic, and the like;

(9) diseases demanding protection of nerves and cells, including cardiacarrest, spinal cord injury, intermittent claudication, ischemic diseases(including angina pectoris, cardiac infarction, cerebral apoplexy, headinjury, etc.) and the like;

(10) endocrine diseases, including not only diabetes but also diabeticretinopathy, diabetic nephropathy, diabetic neurosis, amyloidosis,pancreatitis, thyroiditis, obesity, prostatomegaly, and the like;

(11) autoimmune diseases, including systemic lupus erythematosus (SLE),atrophic gastritis, thyroid diseases, glomerular nephritis, orchitis,adrenal diseases, hemolytic anemia, oophoritis, and the like;

(12) cardiovascular diseases, including hypertension, angina pectoris,heart failure, myocarditis, external epicarditis, endocarditis,valvulitis, and the like;

(13) vessel and blood-system diseases, including angiitis, aneurysm,endoangiosis, thromboangiitis, granulomatosis, cerebrovascular angiitis,arteriosclerosis, periangitis, leukopenia, thrombocytopenia, Boeck'ssarcoid, and the like;

(14) diseases related to immune reactions or allergic responses,including contact dermatitis, serum sickness, drug allergy,Goodpasture's syndrome, lymphoma, rheumatic fever, AIDS, anaphylacticshock and the like; and

(15) other diseases, disorders or abnormal states, including glaucoma,spastic paralysis, impotence, diseases or illness accompanied with pain(contusion, headache, etc.), neck-shoulder-arm syndrome, nephropathy,renal insufficiency, hepatic insufficiency, obesity, female sterility,alopecia, etc.

ADVANTAGEOUS EFFECTS BY THE PRESENT INVENTION

The present invention can provide PDE IV inhibitors. The instantinventive compounds have excellently potent inhibitory action toward PDEIV. The inventive compounds inhibit PDE IV predominantly present inairway smooth muscle cells and inflammatory cells, allowing theelevation of cAMP levels in said cells in order to relax the airwaysmooth muscles and simultaneously suppress the activation ofinflammatory cells. Further, since it is perceivable that there is agreat difference between dose levels for pharmacological actions andthose for inhibition of drug metabolizing enzymes in the inventivecompounds, it is considered that the present invention allows theproduction of excellently pharmacologically-effective and highly safeanti-asthmatic agents and prophylactic and/or therapeutic agents forCOPD.

The above objectives and other objectives, features, advantages, andaspects of the present invention are readily apparent to those skilledin the art from the following disclosures. It should be understood,however, that the description of the specification including thefollowing best modes of carrying out the invention, examples, etc. isillustrating preferred embodiments of the present invention and givenonly for explanation thereof. It will become apparent to the skilled inthe art that a great number of variations and/or alterations (ormodifications) of this invention may be made based on knowledge from thedisclosure in the following parts and other parts of the specificationwithout departing from the spirit and scope thereof as disclosed herein.All of the patent publications and reference documents listed herein forillustrative purposes are hereby incorporated by reference into thepresent disclosure.

BEST MODES OF CARRYING OUT THE INVENTION

The present invention provides PDE IV-inhibitorypyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives (1), or saltsthereof, having an unsubstituted or optionally substituted phenyl,pyridyl, 1-oxypyridyl or thienyl group via 1 to 3 methylene chains onthe 3 position of the pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one ringwhich may be unsubstituted or optionally substituted on the 1 positionthereof, and pharmaceutical compositions comprising at least one memberselected from the aforementioned compounds and pharmaceuticallyacceptable salts thereof. The present invention also provides potentdrugs with advantageous actions.

The definitions for the compounds of the above-defined formula (1) willbe given below in detail.

The term “halogen” as used herein refers to fluorine, chlorine, bromine,and the like.

The term “lower alkyl” refers to alkyl containing 1 to 4 carbon atoms,such as methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, sec-butyland t-butyl.

The term “lower alkoxy” refers to alkoxy containing 1 to 4 carbon atoms,such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy,sec-butoxy and t-butoxy.

The term “lower alkylcarbonyloxy” refers to alkylcarbonyloxy containing2 to 5 carbon atoms, such as acetoxy, ethylcarbonyloxy,propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, sec-butylcarbonyloxy and t-butylcarbonyloxy.

The term “lower alkoxycarbonyl” refers to alkoxycarbonyl containing 2 to5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl.

The term “carboxy-lower alkylene” refers to carboxy-lower alkyleneconstituted of carboxy in combination with straight-chain alkylenecontaining 1 to 4 carbon atoms, such as carboxymethylene,carboxyethylene, carboxytrimethylene, and carboxytetramethylene.

The term “lower alkoxycarbonyl-lower alkylene” refers toalkoxycarbonyl-lower alkylene constituted of alkoxycarbonyl containing 2to 5 carbon atoms in combination with straight-chain alkylene containing1 to 4 carbon atoms, such as methoxycarbonylmethylene,ethoxycarbonylmethylene, propoxycarbonylmethylene,isopropoxycarbonylmethylene, n-butoxycarbonylmethylene,isobutoxycarbonylmethylene, sec-butoxycarbonylmethylene,t-butoxycarbonylmethylene, methoxycarbonylethylene,ethoxycarbonylethylene, propoxycarbonylethylene,isopropoxycarbonylethylene, n-butoxycarbonylethylene,isobutoxycarbonylethylene, sec-butoxycarbonylethylene,t-butoxycarbonylethylene, methoxycarbonyltrimethylene,ethoxycarbonyltrimethylene, propoxycarbonyltrimethylene,isopropoxycarbonyl-trimethylene, n-butoxycarbonyltrimethylene,isobutoxycarbonyltrimethylene, sec-butoxy-carbonyltrimethylene,t-butoxycarbonyltrimethylene, methoxycarbonyl-tetramethylene,ethoxycarbonyltetramethylene, propoxy-carbonyltetramethylene,isopropoxycarbonyltetramethylene, n-butoxycarbonyltetramethylene,isobutoxycarbonyl-tetramethylene, sec-butoxycarbonyltetramethylene, andt-butoxycarbonyltetramethylene.

The term “lower alkylsulfonyl” refers to alkylsulfonyl containing 1 to 4carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyland t-butylsulfonyl.

The term “lower alkylsulfonylamino” refers to alkylsulfonylaminocontaining 1 to 4 carbon atoms, such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino andt-butylsulfonylamino.

Representative examples of compounds of the invention include thefollowing:

-   5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   1-methyl-5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-phenyl-3-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-(3-nitrophenyl)-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-(3-aminophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(4-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(4-methylphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2-thienylmethyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(3,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(3-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(2-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-[2-(3-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-carboxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(3-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(3-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(2-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-acetoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-(4-methanesulfonylaminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   5-phenyl-3-[2-(2-ureidophenyl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one-   3-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-(3-carboxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-phenyl-3-(3-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   5-(3-aminophenyl)-3-benzyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one-   3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

As used herein, “the compound(s) of the present invention” may includesalts thereof, hydrates and solvates thereof, a variety of prodrug formsderived from functional groups existing in compound molecules. Theprodrugs of the compounds according to the present invention includethose compounds which can be transformed in vivo, for example, bymetabolic processes, including hydrolysis, oxidation, reduction,trans-esterification, and the like, to yield the parent compounds of theformula (1), etc. Representatives of such prodrugs are ester-, ether-,amide-, alcohol-, and amine-derivatives thereof. Preferred compoundsaccording to the present invention have specific inhibitory propertiesagainst PDE IV.

Some of the compounds of the present invention may exist in more thanone tautomeric form. This invention extends to all tautomeric forms. Thecompounds of the instant invention may also contain one or pluralasymmetric carbon atoms and thus give rise to optical isomers such as(R)- and (S)-isomers, racemates, diastereoisomers, etc. The presentinvention includes all such possible isomers, and their racemic andresolved, enantiomerically pure forms, as well as all mixtures thereof.

Examples of the aforementioned tautomers include a compound of thefollowing general formula (1-a) wherein A, m and R¹ have the samemeanings as defined above, and a compound of the following generalformula (1-b) wherein A, m and R¹ have the same meanings as definedabove:

The compounds of the invention may be isolated in the form of hydrates,solvates with, for example, ethanol and the like, and a variety ofcrystalline substances.

The present invention also encompasses pharmaceutically acceptable saltsof the naphthyridine derivative having the formula (1). Such saltsinclude those formed from any of medically or pharmaceuticallyutilizable non-toxic or low toxic inorganic or organic acids and bases.Examples of the salts are hydrochloride, hydrobromate, sulfate, acetate,propionate, citrate, succinate, tartrate, methanesulfonate,p-toluenesulfonate, etc.; and alkali metal salts (e.g., sodium salts,potassium salts), alkali earth metal salts (e.g., calcium salts,magnesium salts), ethylene diamine salts, etc.

The compounds of the present invention can be prepared by one of variousroutes. For instance, the compounds of the formula (1) can be preparedby one of the following schemes or modifications thereof:

Briefly, the compounds of the formula (1) wherein A, m, R¹ and R² havethe meanings given above can be prepared by condensing a compound of theformula (2) wherein A, m, and R¹ have the meanings given above with acompound of the formula (3) wherein R² has the meaning given above, or ahydrate or salt thereof. The reaction can be conducted in the presenceof or in the absence of a solvent. When the reaction is conducted insolvents, it is often convenient to use conventional solvents which arefree from any adverse action on the reaction. Examples of such solventsare methanol, ethanol, isopropyl alcohol, acetic acid, propionic acid,diethyl ether, tetrahydrofuran (THF), chloroform, dichloromethane,dimethyl sulfoxide, N,N-dimethylformamide, N,N-diphenylformamide,sulfolane, etc. Preferred examples of such solvents are ethanol,N,N-dimethylformamide, acetic acid, etc. The reaction temperature rangeis about 0° C. to 200° C. and preferably room temperature to about 160°C.

The compounds, wherein the substituent group on the phenyl, pyridyl,1-oxypyridyl, or thienyl group for A is selected from the groupconsisting of hydroxyl, acetoxy, amino, carboxyl, carboxy-lower alkyleneand lower alkylsulfonylamino, can be derived from the compound of theformula (1) by hydrolysis, oxidation, reduction or one of other variousconventional methods which the artisan in the art can utilize. Thecompounds wherein R¹ is hydroxyl, amino or carboxyl can be derived fromthe compound of the formula (1) by one of various conventional methodswhich the artisan in the art can utilize.

In the aforementioned Scheme (1), the compounds of the formula (2) canbe prepared according to one of the following scheme (II) andmodifications thereof:

Briefly, a compound of the formula (4) wherein R¹ has the meaning givenabove can react with a compound of the formula (5) wherein A and m havethe meanings given above in the presence of polyphosphoric acid toproduce the compound of the formula (2).

The compounds of the formula (2) can be prepared according to one of thefollowing scheme (III) and modifications thereof:

Briefly, a compound of the formula (4) wherein R¹ has the meaning givenabove can react with a compound of the formula (6) wherein A and m havethe meanings given above in the presence of sodium hydride to produce acompound of the formula (7). Next, the resulting compound of the formula(7) can be treated with a cyanide such as lithium cyanide, sodiumcyanide and potassium cyanide, a base such as triethylamine, in thepresence of crown ether such as 15-crown-5 ether, 12-crown-4 ether and18-crown-6 ether, in a solvent such as toluene, to produce the compoundof the formula (2).

In the aforementioned Scheme (III), a compound of the formula (4) canreact with a compound of the formula (6) wherein m=1 in the presence ofsodium hydride at an excess equivalent (preferably 2 to 3 equivalents)to produce directly the compound of the formula (2) without passingthrough the compound of the formula (7).

In the aforementioned Schemes (II) and (III), the compounds of theformula (4) can be prepared by one of known methods (e.g., JP, A,61-246183 (1986); J. Med. Chem., 31, 2108 (1988)) or modificationsthereof.

The compounds of the formula (4) can be prepared by one of the followingScheme (IV) and modifications thereof:

Briefly, a compound of the formula (8) can be converted according to oneof modifications of known methods (JP, A, 5-194515 (1993)) into acompound of the formula (10) wherein R¹ has the meaning given above viaa compound of the formula (9). Next, the compound of the formula (10)can react with alkali metal hydroxide, or alkali earth metal hydroxide,(for example, potassium hydroxide) to produce the compound of theformula (4).

In the aforementioned Scheme (IV), the compounds of the formula (8) canbe prepared by one of known methods (e.g., WO, A, 01/42244) ormodifications thereof.

The compounds of the present invention are potent PDE IV inhibitors. Thecompounds of the present invention are thus of use in the prophylaxisand treatment of diseases and abnormal states directly or indirectlyrelated to PDE IV actions. In particular, the compounds of the presentinvention are effective as prophylactic or therapeutic agents fordiseases and conditions associated with an abnormal enzymatic orcatalytic activity of PDE IV. The compounds of the present invention areuseful as prophylactic or therapeutic agents or drugs for especially theprophylaxis and treatment of:

-   -   (1) respiratory diseases, including, for example, bronchial        asthma (including chronic bronchial asthma and atopic asthma),        acute bronchitis, chronic bronchitis, asthmatic bronchitis,        pneumonic diseases, pulmonary emphysema, chronic obstructive        pulmonary disease (COPD), acute respiratory distress syndrome        (ARDS), and the like;    -   (2) inflammatory diseases, including, for example, atopic        dermatitis, conjunctivitis, urticaria, acquired immunodeficiency        syndrome (AIDS), keloid formation, rhinitis, iridocyclitis,        gingivitis, periodontitis, dentoalveolitis, gastritis,        ulcerative colitis, Crohn's disease, gastrointestinal ulcer,        esophagitis, myositis, encephalitis, myasthenia gravis, multiple        sclerosis, neuritis, hepatitis, scar tissue formation, nephritis        (including proliferative nephritis), peritonitis, pleurisy,        scleritis, scleroderma, scalds or burns, and the like;    -   (3) systemic or local joint diseases, including, for example,        osteoarthritis, gouty arthritis, rheumatoid arthritis, malignant        rheumatism, psoriatic arthritis, and the like;    -   (4) inflammatory conditions associated with organ        transplantation, etc., including, for example, reperfusion        injury, graft versus host reaction, and the like;    -   (5) diseases or symptoms related to urination, including, for        example, diabetes insipidus, urethritis, urinary incontinence,        cystitis, irritable bladder, neurogenic bladder, uremia,        uriniferous tubular disorder, pollakiuria, ischuria, and the        like;    -   (6) diseases or abnormal conditions related to, for example,        tumor necrosis factor (TNF) (TNF-α, etc.) and other cytokines        (for example, IL-1, IL-4, IL-6, etc.), including psoriasis,        rheumatoid arthritis, ulcerative colitis, Crohn's disease,        septicemia, septic shock, endotoxic shock, gram-negative        bacillus sepsis, toxic shock syndrome, nephritis, hepatitis,        infection (induced by bacteria and viruses), circulatory failure        (heart failure, arteriosclerosis, myocardial infarction,        cerebral apoplexy), and the like;    -   (7) proliferative diseases, including, for example, malignant        tumors, leukemia, proliferative dermal diseases (keratosis and        various types of dermatitides), connective tissue diseases and        the like;    -   (8) diseases related to nervous function abnormality, including,        for example, impaired learning, memory and recognition        associated with neurodegenerative disorders such as Alzheimer's        disease and Parkinson's disease, multiple lateral sclerosis,        senile dementia, amyotrophic lateral sclerosis, acute        demyelinating neuritis, muscular dystrophy, and the like;    -   (9) diseases related to abnormality of mental functions,        including, for example, manic-depressive psychosis, schizoid,        anxiety, panic, and the like;    -   (10) diseases demanding protection of nerves and cells,        including, for example, cardiac arrest, spinal cord injury,        intermittent claudication, ischemic diseases (including angina        pectoris, cardiac infarction, cerebral apoplexy, head injury,        etc.) and the like;    -   (11) endocrine diseases, including not only diabetes but also        diabetic retinopathy, diabetic nephropathy, diabetic neurosis,        amyloidosis, pancreatitis, thyroiditis, obesity, prostatomegaly,        and the like;    -   (12) autoimmune diseases, including, for example, systemic lupus        erythematosus (SLE), atrophic gastritis, thyroid diseases,        glomerular nephritis, orchitis, adrenal diseases, hemolytic        anemia, oophoritis, and the like;    -   (13) cardiovascular diseases, including, for example,        hypertension, angina pectoris, heart failure, myocarditis,        external epicarditis, endocarditis, valvulitis, and the like;    -   (14) vessel and blood system diseases, including, for example,        angiitis, aneurysm, endoangiosis, thromboangiitis,        granulomatosis, cerebrovascular angiitis, arteriosclerosis,        periangitis, leukopenia, thrombocytopenia, Boeck's sarcoid, and        the like;    -   (15) diseases related to immune reactions or allergic responses,        including, for example, contact dermatitis, serum sickness, drug        allergy, Goodpasture's syndrome, lymphoma, rheumatic fever,        AIDS, anaphylactic shock and the like; and    -   (16) other diseases, disorders or abnormal states, including,        for example, glaucoma, spastic paralysis, impotence, diseases or        illness accompanied with pain (contusion, headache, etc.),        neck-shoulder-arm syndrome, nephropathy, renal insufficiency,        hepatic insufficiency, obesity, female sterility, alopecia, etc.

It is known that the aforementioned diseases and abnormal conditionswould be or are directly or indirectly related to PDE IV.

Particularly, the compounds of the present invention act as prophylacticand/or therapeutic drugs for:

-   -   (i) respiratory diseases (such as bronchial asthma including        chronic bronchial asthma and atopic asthma; acute bronchitis;        chronic bronchitis; asthmatic bronchitis; pneumonic diseases;        pulmonary emphysema; chronic obstructive pulmonary disease        (COPD); acute respiratory distress syndrome (ARDS); etc.); and    -   (ii) inflammatory diseases (such as atopic dermatitis;        conjunctivitis; urticaria; acquired immunodeficiency syndrome        (AIDS); keloid formation; rhinitis; iridocyclitis; gingivitis;        periodontitis; dentoalveolitis; gastritis; ulcerative colitis;        Crohn's disease; gastrointestinal ulcer; esophagitis; myositis;        encephalitis (such as myasthenia gravis, multiple sclerosis and        neuritis); hepatitis; scar tissue formation; nephritis including        proliferative nephritis; peritonitis; pleurisy; scleritis;        scleroderma; scalds or burns; etc.)        Among them, the compounds of the present invention are most        preferably effective as prophylactic and/or therapeutic drugs        for bronchial asthma and COPD.

It is also verified that the compounds of the present invention aresignificantly less inhibitory toward drug-metabolizing enzymes such asCYP2D6 and CYP3A4 than the prior art PDE IV inhibitors. In other words,as illustrated herein below in assay examples, the prior art PDE IVinhibitors have a slight difference between theirpharmacologically-effective dose (such as anti-asthmatic dose) and theireffective dose for inhibiting drug-metabolizing enzymes, or inhibitdrug-metabolizing enzymes at a less dose than they exert apharmaceutical action, etc., whereby it is anxious to limit theirclinical applications. In contrast, the compounds of the presentinvention have unexpectedly much higher dose levels for inhibitoryaction on the drug-metabolizing enzymes than for pharmacological action,and extremely advantageous in view of safety.

Thus, the present invention encompasses pharmaceutical compositionscomprising an effective amount of at least one member selected from theabove-defined compounds (1) and pharmaceutically acceptable saltsthereof, including not only PDE IV-specific inhibitors but alsoanti-asthmatic agents and prophylactic or therapeutic agents for COPD.

As aforementioned, since PDE IV is predominantly in vivo located inairway smooth muscle cells and inflammatory cells, the compounds of thepresent invention inhibit PDE IV in these cells, thereby exerting abronchodilator action via relaxing airway smooth muscles, together withan anti-inflammatory action through suppressing inflammatory cellactivation. Hence, the compounds of the present invention are widelyeffective in ameliorating a variety of undesirable responses andsymptoms raised with regard to asthma and COPD.

The following disclosure is to illustrate an anti-asthmatic action, oneof actions produced by the compounds of the present invention in detail:

It is known that a series of responses, such as an immediate asthmaticresponse, a delayed asthmatic response, and a hypersensitive airwayresponse, are induced when an asthmatic patient inhales antigens whichcause the disease.

First, the immediate asthmatic response that begins immediately afterinhalation of antigens is a typical airway smooth muscle constrictivereaction induced by chemical mediators (including histamine,leukotrienes, etc.) which are released from mast cells as a result ofantigen-antibody interactions. Later the delayed asthmatic response isobserved, which occurs within 4 to 24 hours after the inhalation ofantigens. For its pathological states, an infiltration of inflammatorycells into lung tissues, airway mucosa edema, etc. are observed.Thereafter, the hypersensitive airway response is further elicited,which occurs within 1 to 14 days after the inhalation of antigens and isa state wherein the airway reactivity is increased. In such a stage,even quite mild stimuli lead to constriction of the airway andoccurrence of serious airway obstruction.

As aforementioned, various responses and symptoms appear in asthma. Thecompounds of the present invention can exert an excellent inhibitoryand/or ameliorating activity on such responses and symptoms at eachstage, relying on their bronchodilator and anti-inflammatory actionsbased on the inhibition of PDE IV.

Diseases and abnormal states to be targeted by the therapy using thecompounds of the present invention include the aforementioned diseasesand abnormal conditions, preferably diseases and abnormal conditionsaccompanied with respiratory dysfunctions and inflammation at the areaof bronchus and airway. Embodiments of such diseases include bronchialasthma including chronic bronchial asthma and atopic asthma, acutebronchitis, chronic bronchitis, asthmatic bronchitis, pneumonicdiseases, pulmonary emphysema, chronic obstructive pulmonary disease(COPD), acute respiratory distress syndrome (ARDS), and other bronchusand airway inflammatory states, etc.

For patients with the foregoing diseases, disorders, and abnormalstates, the compounds of the present invention can be used independentlywithout any additives, but preferably in admixture with any ofpharmaceutically acceptable additives. The compounds of the presentinvention may be orally, parenterally (including by injection),topically (including by inhalation) administered as pharmaceuticalcompositions or formulations. One or more components selected from knownpharmaceutical additives (hereinafter also referred to “pharmaceuticalingredient(s)”) can be employed in the aforementioned pharmaceuticalcompositions or formulations for any of administration routes.Embodiments of such known pharmaceutical additives may be suitablyselected, according to administration routes and applications ofpharmaceutically formulated forms, from components as disclosed in, forexample, (1) “Iyakuhin Tenkabutsu Handbook (Handbook of PHARMACEUTICALEXCIPIENTS)”, Maruzen Publishing Company, Japan (1989); (2) “IyakuhinTenkabutsu Jiten (Pharmaceutical Excipient Dictionary)”, First Edition,K.K. Yakuji Nippo Sha, Japan (1994); (3) “Iyakuhin Tenkabutsu JitenTsuiho (Pharmaceutical Excipient Dictionary, Supplement)”, FirstEdition, K.K. Yakuji Nippo Sha, Japan (1995); and (4) “Yakuzaigaku(Pharmaceutics)”, 5th Edition, K.K. Nankodo, Japan (1997).

For oral administration, the aforementioned additives are anypharmaceutical ingredients as long as they are suitable for oral drugsand the intended purposes according to the present invention. Usually,the pharmaceutical additive is selected from conventional pharmaceuticalingredients such as vehicles, binders, disintegrants, lubricants, andcoating agents. The oral formulations of the present invention includetablets, capsules, granules, fine granules, powders, syrups, etc. Theoral drug includes controlled-release system preparations wherein the invivo release of the compound of the present invention which is containedas the active ingredient is controlled using any of known pharmaceuticalingredients (for example, immediate-release preparations,sustained-release preparations, etc.).

The aforementioned oral drug may include enteric preparations. In somecases, it is rather preferable that the oral drugs are prepared in theform of such enteric preparations. Such enteric preparations includecapsule formulations wherein any of enteric coating agents is containedas an ingredient for their coat, said enteric coating agent beingselected from cellulose phthalate, hydroxypropyl methylcellulosephthalate, and methyl methacrylate-methacrylic acid copolymers, etc.

For injection, the additives include pharmaceutical ingredients suitablefor aqueous or non-aqueous injections. Usually, the additive is selectedfrom conventional pharmaceutical ingredients such solubilizers, solutionadjuvants, suspending agents, buffers (pH regulators), stabilizers andpreservatives. In addition, it may be selected from conventionalingredients suitable for preparing powders for injection, which are usedin solution or suspension when administered.

When administered topically, for example, via inhalation, etc., theaforementioned additives as used herein include any of pharmaceuticalingredients known in the art, such as solution adjuvants, stabilizers,buffers, suspending agents, emulsifying agents, and preservatives.Embodiments of inhalants include aerosols. Aerosol-producing techniquesare any of types including a spraying type wherein active drugingredients are packed together with propellants such as fluorocarbonalternatives into a sealed container and sprayed, and a nebulizer oratomizer type using a pressured gas, such as carbon dioxide andnitrogen, filled in a container different from that for active drugingredients.

Desired oral drugs, injections or drugs for topical applications(including inhalants) comprising the compound of the present inventionin admixture with the aforementioned ingredient can be preparedaccording to manufacturing methods known per se, for example, thosedescribed in The 14th Pharmacopoeia of Japan (JPXIV) or appropriatelymodified ones.

The pharmaceutical compositions (drugs) of the present invention areadministered to mammals, particularly including human. The doses ofthese compounds or salts thereof are usually about 0.1 to 1,000 mg (perday), preferably about 0.1 to 500 mg (per day) for oral administration;usually about 0.01 to 200 mg (per day), preferably about 0.05 to 100 mg(per day) for injection; and usually about 0.01 to 200 mg (per day),preferably about 0.05 to 100 mg (per day) for topical applications.Specific administration routes and dose levels (including the optimaldose) for any particular patient will be employed depending upon avariety of factors including the patient's conditions (general health,the severity of the particular disease or symptom undergoing therapy,the presence or absence of complications thereof, etc.), the age, sex,body weight, and the like.

EXAMPLES, ETC.

Described below are examples, including assay examples, syntheticexamples and formulation examples, of the present invention which areprovided only for illustrative purposes, and not to limit the scope ofthe present invention. All the examples were carried out or can becarried out, unless otherwise disclosed herein specifically, by standardtechniques which are well known and conventional to those skilled in theart.

Assay Examples

Described below are examples of pharmacological assays for the efficacyand safety of the compounds (1) of the present invention wherein theirprotocols and results are provided.

Assay Example 1 PDE IV Inhibition <Protocol>

The assays for PDE IV activity were conducted according to Nicholson etal. method (Br. J. Pharmacol., 97, 889 (1989)).

PDE IV isozymes as used herein were separated from U937 culture cells byusing an anion exchange chromatography. Type IV PDE isozyme was admixedwith ethylene glycol (EG) to adjust the final EG concentration to 30%,then stored at −20° C. and diluted when used. The enzymatic activity forPDE IV was measured using cAMP as a substrate.

[³H]-cAMP (962 GBq/mmol; Amersham, 25 μl (100,000 cpm)) was addedtogether with PDE IV isozyme (25 μl) to an incubation buffer solutionwith the composition given below to adjust the total volume to 250 μl.Each test compound was dissolved in DMSO to adjust the finalconcentration to 1% (2.5 μl/tube).

Incubation Buffer Solution (pH7.5):

Tris-HCl (50 mM), magnesium chloride (6 mM), dithiothreitol (2.5 mM),5-nucleotidase (4 μg/ml), bovine serum albumin (0.23 mg/ml), and cAMP (1μM).

A mixture of the aforementioned test compound solution and the buffersolution was incubated at 30° C. for 20 minutes. The reaction wasquenched by admixing with 1 ml of anion exchange resin slurry (AG1-X8,200-400 meshes, chloride form; Bio-Rad) to absorb unreacted substrates.After the reaction stopped, the mixture was centrifuged at 800×g for 10minutes, and the resulting supernatant was collected with vials in 250μl aliquots. To each vial was added 5 ml of ACS-II (scintillator,Amersham). The radioactivity was measured with a liquid scintillatorcounter for [³H]-adenosine and set as the PDE IV activity.

The % inhibition was calculated for test compounds, and IC₅₀ (theconcentration of each test compound required for 50% inhibition) wasobtained by Probit method. The results are shown in Table 1. Rolipram[(−)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone], alreadyknown as the PDE IV inhibitor in the prior art, was used for thereference compound in this assay.

TABLE 1 Inhibition of PDE IV Test Compounds (IC₅₀: μM) Example No. 50.067 Example No. 6 0.025 Example No. 9 0.084 Example No. 13 0.031Example No. 14 0.057 Example No. 21 0.088 Example No. 22 0.026 ExampleNo. 23 0.082 Example No. 26 0.020 Example No. 27 0.021 Example No. 300.049 Example No. 32 0.028 Example No. 33 0.068 Example No. 41 0.089Example No. 43 0.086 Example No. 46 0.032 Example No. 53 0.028 ExampleNo. 56 0.023 Example No. 58 0.035 Rolipram 0.19

<Conclusion>

As seen in Table 1, it has been verified that the compounds of thepresent invention inhibit potently PDE IV.

Assay Example 2 Inhibition of Antigen-Induced Immediate AsthmaticResponse Anti-Asthmatic Action <Protocol> (1) Active Sensitization ofGuinea Pigs

Male Hartley outbred guinea pigs were sensitized by administeringintraperitoneally physiological saline (0.5 ml) containing ovalbumin (1mg, antigen) and 5×10⁹ inactivated Bordetella pertussis dead cells(adjuvant). Eleven to thirteen days after the first sensitization, 0.05ml of an ovalbumin solution (1 mg/ml) (ovalbumin is dissolved inphysiological saline) was administered to the lateroabdominal region ofeach guinea pig intracutaneously. An establishment of sensitization waschecked relying on cutaneous reaction. Only guinea pigs whereinsignificant reddening responses occurred 5 to 10 minutes later wereemployed in the next measurement test for airway resistance.

(2) Measurement for Airway Resistance in Actively Sensitized-Guinea Pigs

The guinea pigs (3 animals per group) actively sensitized in the abovestep (1) were employed to measure for their airway pressure according toKonzett-Rossler method (Arch. Exp. Path. Pharmakol., 195, 71 (1940)).

Thirteen days after the final sensitization, guinea pigs fastedovernight, and were on the next day anesthetized with a pentobarbitalsolution (30 mg/1.2 ml/kg, dissolved in physiological saline,intraperitoneal administration). After the guinea pigs were fixed in asupine position, their trachea was incised followed by insertion withone port of a 4-port cannula. Among the remaining 3 ports, 2 ports wereconnected to an artificial respirator (Model 683, Harvard). The animalswere ventilated with 10 ml/kg of air per ventilation at a rate of 60beats/min via the artificial respirator from the cannula. One portremainder was connected to a respiratory amplifier (AR-601G, NihonKohden, Japan) via an airflow resistance tube (TV-241T, Nihon Kohden,Japan) and a differential pressure transducer (TP-602T, Nihon Kohden,Japan) connected with a control box (RY-111S, Nihon Kohden, Japan). Froma catheter inserted into a left carotid artery, blood pressures weremonitored with a blood pressure measurement unit (AP641G, NEC Corp.,Japan) via a blood pressure transducer (TP-300T, Nihon Kohden, Japan),and heart rates were recorded on a thermal recorder (WT-685G, NihonKohden, Japan), relying on blood pressure pulse waves after being led toa cardiograph unit (AT601G, Nihon Kohden, Japan).

After airway pressure became stable, an ovalbumin solution (1 mg/ml,dissolved in physiological saline) was administered at a dose of 1 ml/kgvia a tube with which the right jugular vein of guinea pigs wascannulated. Each area under airway pressure-time curve (AUC) wasobtained by measuring amplitudes of the airway pressure prior to theantigen-challenge, 1, 2, 3, 4, 5, 11, 15 and 20 minutes post-challenge,and each percent increase (%) in airway resistance was furthercalculated according to the following equation:

${{Percent}\mspace{14mu} {Increase}\mspace{14mu} {in}\mspace{14mu} {Airway}\mspace{14mu} {Resistance}\mspace{14mu} (\%)} = {\left( {\frac{{AUC}\mspace{14mu} {for}\mspace{14mu} 20\mspace{14mu} \min \mspace{14mu} {after}\mspace{14mu} {Antigen}\text{-}{Challenge}}{\begin{matrix}{{Basal}\mspace{14mu} {Respiratory}\mspace{14mu} {Pressure}} \\{{AUC}\mspace{14mu} {for}\mspace{14mu} 20\mspace{14mu} \min \mspace{14mu} {after}\mspace{14mu} {Antigen}\text{-}{Challenge}}\end{matrix}} - 1} \right) \times 100}$

Each test compound was suspended in 0.5% CMC-Na solution andadministered orally with an oral sound at a dose of 0.03 to 20 mg/2ml/kg 60 minutes prior to the antigen-challenge. Control groups receivedonly 0.5% CMC-Na solution in an equivalent amount. Thepentobarbital-anesthetization and tracheal incision were conducted 30minutes prior to the antigen-challenge.

Each percent reduction of increase in airway resistance (each testcompound-administered group versus control group) was calculatedaccording to the equation given below. ED₅₀ was obtained by Probitmethod. The results are shown in Table 2. Rolipram, SB207499(cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid; disclosed in J. Med., Chem., 41, 821 (1998), etc.), andRoflumilast(3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide)were used for the reference compounds in this assay.

${{Percent}\mspace{14mu} {Reduction}\mspace{14mu} {of}\mspace{14mu} {Increase}\mspace{14mu} {in}\mspace{14mu} {Airway}\mspace{14mu} {Resistance}\mspace{14mu} (\%)} = {100 - {\left( \frac{\begin{matrix}{{Percent}\mspace{14mu} {Increase}\mspace{14mu} {in}\mspace{14mu} {Airway}\mspace{14mu} {Resistance}} \\\left( {{Test}\mspace{14mu} {Compound}\text{-}{Administered}\mspace{14mu} {Group}} \right)\end{matrix}}{\begin{matrix}{{Percent}\mspace{14mu} {Increase}\mspace{14mu} {in}\mspace{14mu} {Airway}} \\{{Resistance}\mspace{14mu} \left( {{Control}\mspace{14mu} {Group}} \right)}\end{matrix}} \right) \times 100}}$

TABLE 2 Inhibition of Asthmatic response Test Compounds ED₅₀: mg/kgorally Example No. 9 0.16 Example No. 33 0.33 Roflumilast 0.66 Rolipram0.51 SB207499 >20

<Conclusion>

As seen in Table 2, it has been verified that the compounds of thepresent invention exert an excellent inhibitory action onantigen-induced immediate asthmatic responses.

Assay Example 3 Inhibition of TNF-α Production in Galactosamine- andLipopolysaccharide (LPS)-Stimulation <Protocol>

A suspension of each test compound in 0.5% CMC-Na solution wasadministered orally to C3H/HeN mice at a dose of 0.10 to 10 mg/kg. Onehour later, the animals received intravenously galactosamine at a doseof 800 mg/kg and LPS at a dose 5 μg/kg to raise the induction of TNF-αproduction. One hour later after the galactosamine- andLPS-administration, amounts of TNF-α in serum samples were measured byELISA, and ED₅₀ was obtained. The results are shown in Table 3.Roflumilast and SB207499 were used for the reference compounds in thisassay.

TABLE 3 Inhibition of TNF-α production Test Compounds ED₅₀: mg/kg orallyExample No. 9 0.22 Example No. 33 0.10 Roflumilast 0.26 SB207499 3.3

<Conclusion>

As seen in Table 3, it has been verified that the compounds (ExampleNos. 9 and 33) have a better inhibitory action on TNF-α production.

Assay Example 4 Inhibition of Drug-Metabolizing Enzymes <Protocol>

The inhibitory effect on CYP2D6 and CYP3A4 was determined using HighThroughput Inhibitor Screening Kits: CYP2D6/AMMC and CYP3A4/BFC (bothfrom BD Biosciences, NJ, USA). Briefly, each of NADPH regeneratingsystems, cofactors, and test compounds was dispensed into 96-wellplates, followed by addition of each of fluorescent substrates, AMMC(CYP2D6) or BFC (CYP3A4). To each well were added CYP2D6-expressingsystem microsomes or CYP3A4-expressing system microsomes, and the plateswere incubated at 37° C. for 30 minutes, and then read for fluorescentsignals (CYP2D6: ex=390 nm, em=460 nm; CYP3A4: ex=409 nm, em=538 nmwherein excitation wavelength: ex and emission wavelength: em). Thus,each inhibitory efficacy on enzymes CYP2D6 and CYP3A4 was determined.The results are shown in Table 4. Roflumilast was used for the referencecompound in this assay.

TABLE 4 Inhibition of Drug-Metabolizing Enzymes (IC₅₀: μM) TestCompounds CYP2D6 CYP3A4 Example No. 9 >10 8.5 Example No. 33 >10 6.2Roflumilast 9.1 0.98

<Conclusion>

As seen in Table 4, it has been verified that the compounds (ExampleNos. 9 and 33) are less inhibitory to drug-metabolizing enzymes (CYP2D6and CYP3A4).

Assay Example 5 Inhibition of Lung Eosinophil Infiltration <Protocol>

Hartley guinea-pigs were sensitized by inhaling twice 1% ovalbumin (OVA)in a physiological saline for 10 minutes with a nebulizer (Atom MedicalCorporation, Japan) at an interval of 1 week. The animals were orallygiven a suspension of test compounds at a dose of 0.03 to 3 mg/2 mL/kgone week after the final sensitization. One hour later, the animals wereexposed to antigens by inhalation of 2% OVA in a physiological salinefor 5 minutes with a nebulizer. Thirty minutes before the antigenchallenge, the animals were intraperitoneally pretreated with pyrilamineat a dose of 10 mg/kg to avoid fatality due to anaphylactic shock.Bronchoalveolar lavage fluid (BALF) samples were collected 24 hoursafter the exposure by inhalation of antigens, and eosinophils werecounted.

TABLE 5 Inhibition of Lung Eosinophil Infiltration Test Compounds ED₅₀:mg/kg orally Example No. 9 <0.03 Example No. 33 0.03 Roflumilast 0.36

<Conclusion>

It has been verified that the compounds of the present invention(Example Nos. 9 and 33) are more inhibitory on lung eosinophilinfiltration than Roflumilast.

Assay Example 6 Inhibition of Lung Neutrophil Infiltration <Protocol>

Hartley guinea-pigs were orally received a suspension of test compoundsat a dose of 0.03 to 3 mg/2 mL/kg. One hour later, the animals werereceived 0.1 mg/mL lipopolysaccharide (LPS) in a physiological salinevia an inhalational route with a nebulizer for 30 minutes. Twenty-fourhours after the LPS inhalation, BALF samples were collected, andneutrophils were counted.

TABLE 6 Inhibition of Lung Neutrophil Infiltration Test Compounds ED₅₀:mg/kg orally Example No. 9 0.12 Example No. 33 0.09 Roflumilast 0.98

<Conclusion>

It has been verified that the compounds of the present invention(Example Nos. 9 and 33) are more inhibitory on lung neutrophilinfiltration than Roflumilast.

Assay Example 7 Toxicology Study 1-Week-Administration to Mice<Protocol>

The Compound of the present invention (Example No. 9) was administeredorally to ICR mice (7 animals per group) as a test compound. During oneweek, the mice were observed for the time course of their general healthconditions and measured for their body weight. The test compound wassuspended in 0.5% CMC-Na solution and given orally to the animal at adose of 100 or 300 mg/10 ml/kg in a forced manner.

<Conclusion>

None of the animals were died in every dose group when the test compoundwas administered. No reduction of body weight gains was observed,either. Further, no abnormality was observed for other parameters.

Assay Example 8 Toxicology Study 2-Weeks-Administration to Rats<Protocol>

Each compound of the present invention (Example Nos. 9 and 33) wasadministered orally to rats (6 animals per group) as a test compound.During 2 weeks, the rats were observed for the time course of theirgeneral health conditions and measured for their body weight. The testcompound was suspended in 0.5% CMC-Na solution and given orally to theanimal at a dose of 1, 5, or 25 mg/5 ml/kg in a forced manner.

<Conclusion>

None of the animals were died in every dose group when the testcompounds were administered. No significant reduction of body weightgains was observed, either. Further, no clear abnormality was observedfor other parameters.

Assay Example 9 Emetic Action on Dogs <Protocol>

Beagle dogs received a suspension of each test compound in 0.5% CMC-Nasolution orally at a dose of 1 mg/2 mL/kg. The animals were observed foroccurrence of emesis after the test compound administration.

<Conclusion>

When the instant compounds (Example Nos. 9 & 33 Compounds) were orallyadministered to the beagle dogs, there was no observation for emeticactions at the dose of 1 mg/kg. In contrast, it was found that 2 animalsamong 3 were afflicted with emetic reactions for the test referencecompound, Roflumilast, even at the dose of 1 mg/kg.

In conclusion, it has been verified that the instant compounds, ExampleNos. 9 & 33 Compounds, are less emetic than Roflumilast.

Synthetic Examples

Described below are Synthetic Examples 1 to 28 for the compounds of theformula (2).

Synthetic Example 14-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

(1) A solution of ethyl 3-(pyridin-4-yl)propionate (17.14 g, 96 mmol;synthesized according to WO, A, 01/42244) in aqueous sodium hydroxide(2N, 100 ml) was heated under reflux for 1 hour, cooled, then adjustedpH 4 to 5 with conc. sulfuric acid, filtered to give precipitates whichwere washed with water, and then with hexane, and dried to afford3-(pyridin-4-yl)propionic acid (10.15 g, 70%) as crystals.

¹H NMR (DMSO-d₆) δ: 2.59 (2H, t, J=7.6 Hz), 2.83 (2H, t, J=7.6 Hz),7.25-7.27 (2H, app-d, J=5.9 Hz), 8.44-8.46 (2H, app-d, J=5.9 Hz), 12.21(1H, br)

(2) A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (2.0 g,8.4 mmol; synthesized according to JP, A, 61-246183 (1986)),3-(pyridin-4-yl)propionic acid (19.03 g, 126 mmol, 15 eq.) andpolyphosphoric acid (about 100 ml) was heated overnight at 150° C. whilestirring. The mixture was poured into water with stirring to form asolution while it was occasionally cooled. The operation including 3times washing of the aqueous layer with chloroform, then addition ofsaturated aqueous sodium hydrogen carbonate followed by occasionalextraction with chloroform was repeated until the aqueous layer was madepH3 to 3.5. The organic layers which were collected during neutralizingwere pooled, dried over anhydrous magnesium sulfate, and then evaporatedto give a residue which was purified by flash column chromatography toafford4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(1.59 g, 51%) as crystals.

mp 206-208° C.

¹H NMR (CDCl₃) δ:3.06 (2H, t, J=7.6 Hz), 3.67 (2H, t, J=7.6 Hz),7.20-7.27 (3H, m), 7.23-7.25 (2H, app-d, J=4.3 Hz), 7.47-7.62 (3H, m),8.47-8.49 (2H, app-d, J=4.9 Hz), 8.52-8.58 (2H, m)

Synthetic Example 24-hydroxy-3-[1-oxo-3-(pyridin-3-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

(1) A mixture of 3-(pyridin-3-yl)propenoic acid (10.0 g, 67 mmol), 10%palladium-activated carbon (1 g), methanol (100 mL) and ethanol (100 mL)was stirred overnight under hydrogen atmosphere. The resultant reactionmixture was filtered, evaporated, and dried to give3-(pyridin-3-yl)propionic acid (10.2 g, quantitative).

¹H NMR (DMSO-d₆) δ:2.52 (2H, m), 2.81 (2H, t, J=7.6 Hz), 7.27-7.31 (1H,app-dd, J=4.6 Hz, 7.9 Hz), 7.63-7.67 (1H, app-dt, J=7.9H, 1.7 Hz),8.38-8.40 (1H, app-dd, J=1.7 Hz, 4.6 Hz), 8.44-8.45 (1H, app-d, J=1.7Hz)

(2) The procedure of Synthetic Example 1 was repeated using4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (402 mg, 1.7 mmol;synthesized according to JP, A, 61-246183 (1986)),3-(pyridin-3-yl)propionic acid (3.81 g, 25.2 mmol, 15 eq.) andpolyphosphoric acid (10 ml) to afford4-hydroxy-3-[1-oxo-3-(pyridin-3-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(283 mg, 45%).

mp 219-220° C.

¹H NMR (CDCl₃) δ:3.09 (2H, t, J=7.3 Hz), 3.67 (2H, t, J=7.3 Hz),7.20-7.37 (4H, m), 7.50-7.61 (3H, m), 7.75-7.78 (1H, app-d, J=7.6 Hz),8.46-8.58 (4H, m)

Synthetic Example 34-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

(1) To a suspension of 2-(pyridin-3-yl)acetic acid-hydrochloride (13.2g, 75.6 mmol) in ethanol (100 mL) was added a solution (150 mL) of 0.5mol potassium hydroxide/ethanol, and the mixture was stirred well, thenfiltered to remove potassium chloride, concentrated, and dried to give2-(pyridin-3-yl)acetic acid (10.6 g, quantitative).

(2) The procedure of Synthetic Example 1 was repeated using4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (712 mg, 3.0 mmol;synthesized according to JP, A, 61-246183 (1986)),2-(pyridin-3-yl)acetic acid (8.23 g, 60 mmol, 20 eq.) and polyphosphoricacid (10 ml) to afford4-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(203 mg, 19%).

mp 186-188° C.

¹H NMR (CDCl₃) δ:4.67 (2H, s), 7.21-7.29 (3H, m), 7.53-7.74 (5H, m),8.52-8.55 (2H, app-d, J=7.9 Hz), 8.57-8.59 (2H, app-dd, J=1.7 Hz, 4.6Hz)

Synthetic Example 44-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one

(1) To methyl 2-(3-nitrophenylamino)nicotinate (5.00 g, 18.3 mmol;synthesized according to WO, A, 01/42244) was added 1,2-dichloroethane(90 ml), and the mixture was heated at 80° C. to form a solution. To theresultant solution was added trichloromethyl chloroformate (also called:diphosgene, 6.7 ml, 54.9 mmol) gradually dropwise over about 30 minutes.Three hours later, the mixture was admixed with activated carbon (150mg), heated under reflux for 30 minutes, filtered, then evaporated, anddried under reduced pressure to give a mixture (5.32 g, quantitative)containing 1-(3-nitrophenyl)-2H-pyrido[2,3-d][3,1]oxazin-2,4(1H)-dioneas crystals.

mp 209-212° C. (dec.)

¹H NMR (CDCl₃) δ:7.33-7.38 (1H, app-dd, J=4.9 Hz, 7.9 Hz), 7.70-7.74(1H, app-td, J=1.7 Hz, 7.9 Hz), 7.75-7.81 (1H, app-dt, J=0.7 Hz, 7.9Hz), 8.27-8.28 (1H, app-t, J=2.0 Hz), 8.39-8.43 (1H, app-ddd, J=1.7 Hz,2.0 Hz, 7.9 Hz), 8.51-8.54 (1H, app-dd, J=2.0 Hz, 7.6 Hz), 8.50-8.58(1H, app-dd, J=2.0 Hz, 4.9 Hz)

(2) To a solution of diethyl malonate (2.99 g, 18.7 mmol) indimethylacetamide (28 ml) was added sodium hydride (about 60%, 933 mg,23.3 mmol) with ice-cooling, and the mixture was stirred to form asolution until the production of hydrogen was completed. After theresultant solution was added to a mixture (5.32 g) containing1-(3-nitrophenyl)-2H-pyrido[2,3-d][3,1]oxazin-2,4(1H)-dione withice-cooling, the mixture was stirred for 3 hours at 150° C., cooled toroom temperature, then treated with ethyl acetate, and allowed to stand.The resulting precipitate was filtered off, and washed with ethylacetate. The residue obtained after filtration was dissolved in water,acidified to pH1 with hydrochloric acid to form precipitates which werefiltered off, washed with water, and dried to give3-ethoxycarbonyl-4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one(4.42 g, yield for 2 steps from (1): 66%) as crystals.

mp 309-312° C. (dec.)

¹H NMR (CDCl₃) δ:1.44 (3H, t, J=7.3 Hz), 4.49 (2H, q, J=7.3 Hz),7.24-7.29 (1H, m), 7.60-7.64 (1H, app-ddd, J=1.0 Hz, 2.0 Hz, 7.9 Hz),7.69-7.75 (1H, app-t, J=7.9 Hz), 8.16-8.18 (1H, app-t, J=2.0 Hz),8.33-8.37 (1H, app-ddd, J=1.0 Hz, 2.0 Hz, 7.9 Hz), 8.51 (1H, s),8.52-8.54 (1H, app-dd, J=2.0 Hz, 4.0 Hz), 14.55 (1H, s)

(3) To3-ethoxycarbonyl-4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one(4.42 g, 12.4 mmol) was added an aqueous solution (18 ml) of potassiumhydroxide (2.44 g, 43.4 mmol), and the mixture was heated under refluxovernight, treated with activated carbon (150 mg), refluxed for 10minutes, and filtered off. The resultant solution was acidified to pH1with hydrochloric acid, filtered off to give precipitates which werewashed with water and dried to afford4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one (3.52 g,quantitative) as crystals.

mp 293-295° C. (dec.)

¹H NMR (DMSO-d₆) δ: 5.97 (1H, s), 7.28-7.33 (1H, app-dd, J=4.6 Hz, 7.9Hz), 7.78-7.81 (2H, m), 8.20-8.33 (3H, m), 8.40-8.43 (1H, app-dd, J=2.0Hz, 4.9 Hz), 12.01 (1H, brs)

(4) The procedure of Synthetic Example 1 was repeated using a mixture of4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one (2.5 g, 8.83mmol), 3-(pyridin-4-yl)propionic acid (19.87 g, 131 mmol, 15 eq.;prepared in Synthetic Example 1-(1)) and polyphosphoric acid (about 100ml) to obtain4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one(1.98 g, 54%).

mp 174-177° C.

¹H NMR (CDCl₃) δ:3.05 (2H, t, J=7.3 Hz), 3.63 (2H, t, J=7.3 Hz),7.20-7.22 (2H, app-d, J=5.9 Hz), 7.27-7.31 (1H, app-dd, J=4.6 Hz, 7.9Hz), 7.60-7.64 (1H, app-ddd, J=1.0 Hz, 1.6 Hz, 7.9 Hz), 7.73-7.78 (1H,app-t, J=7.9 Hz), 8.16-8.18 (1H, app-t, J=2.0 Hz), 8.35-8.39 (1H,app-ddd, J=1.0 Hz, 2.3 Hz, 8.2 Hz), 8.47-8.49 (2H, app-d, J=5.9 Hz),8.52-8.54 (1H, app-dd, J=2.0 Hz, 4.6 Hz), 8.55-8.59 (1H, app-dd, J=2.0Hz, 7.9 Hz)

Synthetic Example 54-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2(1H)-one

(1) A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1.19 g,5.0 mmol; synthesized according to JP, A, 61-246183 (1986)) and sodiumhydride (about 60%, 200 mg, 5.0 mmol) was added DMF (10 ml), and theresultant mixture was stirred to form a solution until the production ofhydrogen was completed. Next, after phenylacetyl chloride (0.8 ml, 6mmol) was added, the mixture was stirred for 1 hour at 50° C., treatedwith saturated aqueous sodium hydrogen carbonate, and filtered off togive precipitates which were washed with water and dried to afford1-phenyl-4-phenylacetoxy-1,8-naphthyridin-2(1H)-one (1.34 g, 75%).

mp 179-180° C./DMF-H₂O

¹H NMR (CDCl₃) δ:4.01 (2H, s), 6.77 (1H, s), 7.06 (1H, dd, J=4.9 Hz, 7.9Hz), 7.24-7.28 (2H, m), 7.38-7.60 (8H, m), 7.63 (1H, dd, J=2.0 Hz, 7.9Hz), 8.44 (1H, dd, J=2.0 Hz, 4.9 Hz)

(2) To a mixture of 1-phenyl-4-phenylacetoxy-1,8-naphthyridin-2(1H)-one(1.34 g, 3.7 mmol), triethylamine (379 mg, 3.7 mmol), potassium cyanide(491 mg, 7.5 mmol), and 18-crown-6 (197 mg) was added dry toluene (35ml), and the mixture was stirred at room temperature overnight, admixedwith saturated aqueous sodium hydrogen carbonate and dichloromethane.The organic layer was washed with saturated aqueous sodium hydrogencarbonate, and successively with saturated aqueous sodium chloride. Theorganic layer was collected, dried over anhydrous magnesium sulfate, andevaporated. The resulting residue was purified by flash columnchromatography to afford4-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2(1H)-one(583 mg, 44%) as crystals.

mp 169-170° C.

¹H NMR (CDCl₃) δ:4.64 (2H, s), 7.21 (1H, dd, J=4.6 Hz, 7.9 Hz),7.25-7.38 (7H, m), 7.49-7.64 (3H, m), 8.52 (1H, dd, J=2.0 Hz, 7.9 Hz),8.56 (1H, dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 64-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using phenylpropionylchloride in place of phenylacetyl chloride to obtain4-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 233-234° C. (yield for 2 steps, 51%).

¹H NMR (CDCl₃) δ:3.03 (2H, t, J=7.3 Hz), 3.64 (2H, t, J=7.3 Hz),7.12-7.26 (8H, m), 7.46-7.60 (3H, m), 8.53 (1H, dd, J=2.0 Hz, 7.9 Hz),8.56 (1H, dd, J=2.0 Hz, 4.9 Hz)

Synthetic Example 74-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using4-nitrophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 215-217° C. (yield for 2 steps, 52%).

¹H NMR (CDCl₃) δ:3.14 (2H, t, J=7.3 Hz), 3.68 (2H, t, J=7.3 Hz),7.20-7.25 (3H, m), 7.39-7.42 (2H, app-d, J=8.2 Hz), 7.47-7.62 (3H, m),8.10-8.13 (2H, app-d, J=8.6 Hz), 8.53 (1H, dd, J=1.7 Hz, 7.9 Hz), 8.57(1H, dd, J=1.6 Hz, 4.6 Hz)

Synthetic Example 84-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using4-cyanophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 248-249° C. (yield for 2 steps, 58%).

¹H NMR (CDCl₃) δ:3.09 (2H, t, J=7.3 Hz), 3.65 (2H, t, J=7.3 Hz),7.20-7.26 (3H, m), 7.34-7.37 (2H, app-d, J=8.2 Hz), 7.46-7.62 (3H, m),7.53-7.56 (2H, app-d, J=7.9 Hz), 8.53 (1H, dd, J=1.7 Hz, 7.9 Hz), 8.57(1H, dd, J=1.7 Hz, 4.6 Hz)

Synthetic Example 94-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using3-nitrophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 164-166° C. (yield for 2 steps, 27%).

¹H NMR (CDCl₃) δ:3.14 (2H, t, J=7.3 Hz), 3.68 (2H, t, J=7.3 Hz),7.20-7.25 (3H, m), 7.39-7.45 (1H, app-t, J=7.9 Hz), 7.47-7.61 (4H, m),8.01-8.06 (1H, m), 8.11-8.13 (1H, m), 8.52-8.55 (1H, app-dd, J=2.0 Hz,7.9 Hz), 8.56-8.58 (1H, app-dd, 2.0 Hz, 5.0 Hz)

Synthetic Example 104-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using2-nitrophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 238-240° C. (yield for 2 steps, 58%).

¹H NMR (CDCl₃) δ:3.30 (2H, t, J=7.9 Hz), 3.70 (2H, t, J=7.9 Hz),7.20-7.25 (3H, m), 7.31-7.40 (2H, m), 7.46-7.59 (4H, m), 7.91-7.93 (1H,app-d, J=7.9 Hz), 8.53-8.58 (2H, m)

Synthetic Example 114-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using2-cyanophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 226-227° C. (yield for 2 steps, 52%).

¹H NMR (CDCl₃) δ:3.26 (2H, t, J=7.3 Hz), 3.67 (2H, t, J=7.3 Hz),7.20-7.37 (5H, m), 7.44-7.61 (5H, m), 8.53-8.58 (2H, m)

Synthetic Example 124-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using3-cyanophenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 219-220° C. (yield for 2 steps, 30%).

¹H NMR (CDCl₃) δ:3.06 (2H, t, J=7.3 Hz), 3.64 (2H, t, J=7.3 Hz),7.20-7.25 (3H, m), 7.32-7.38 (1H, t, J=7.6 Hz), 7.45-7.62 (6H, m),8.52-8.55 (1H, dd, J=2.0 Hz, 7.9 Hz), 8.56-8.58 (1H, dd, J=2.0 Hz, 4.6Hz)

Synthetic Example 134-hydroxy-3-[1-oxo-3-(4-methylphenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using4-methylphenylpropionyl chloride in place of phenylacetyl chloride toobtain4-hydroxy-3-[1-oxo-3-(4-methylphenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one,mp 232-234° C. (yield for steps, 22%).

¹H NMR (CDCl₃) δ:2.29 (3H, s), 2.99 (2H, t, J=7.6 Hz), 3.62 (2H, t,J=7.6 Hz), 7.03-7.06 (2H, app-d, J=7.9 Hz), 7.11-7.14 (2H, app-d, J=7.9Hz), 7.18-7.26 (3H, m), 7.46-7.60 (3H, m), 8.50-8.56 (2H, m)

Synthetic Example 144-hydroxy-3-[1-oxo-2-(3-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

To a solution of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (504 mg,2.12 mmol; synthesized according to JP, A, 61-246183 (1986)) in DMF (20ml) was added sodium hydride (60%, 167 mg, 2.0 eq.) while ice-cooling,and the mixture was stirred to form a solution until the production ofhydrogen was completed (for about 30 minutes), Next, after3-methoxyphenylacetyl chloride (410 mg, 2.22 mmol, 1.05 eq.) was added,the mixture was stirred at room temperature, admixed with water,acidified with hydrochloric acid, and then filtered off to giveprecipitates which were washed with water, dried, and then evaporated.The resulting residue was purified by flash column chromatography toafford4-hydroxy-3-[1-oxo-2-(3-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(423 mg, 52%).

mp 173-174° C.

¹H NMR (CDCl₃) δ:3.79 (3H, s), 4.62 (2H, s), 6.81-6.90 (3H, m),7.18-7.29 (4H, m), 7.49-7.64 (3H, m), 8.50-8.54 (1H, app-dd, J=2.0 Hz,7.9 Hz), 8.55-8.58 (1H, app-dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 154-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-methoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(55%), mp 190-191.5° C.

¹H NMR (CDCl₃) δ:3.80 (3H, s), 4.58 (2H, s), 6.80-6.90 (2H, m),7.18-7.30 (5H, m), 7.49-7.63 (3H, m), 8.49-8.53 (1H, app-dd, J=1.9 Hz,8.1 Hz), 8.55-8.57 (1H, app-dd, J=1.9 Hz, 4.9 Hz)

Synthetic Example 164-hydroxy-3-[1-oxo-2-(2-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using2-methoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(2-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(50%), mp 203-205° C.

¹H NMR (CDCl₃) δ:3.78 (3H, s), 4.61 (2H, s), 6.90-6.98 (2H, m),7.12-7.15 (1H, m), 7.19-7.23 (1H, app-dd, J=4.9 Hz, 7.6 Hz), 7.27-7.33(3H, m), 7.49-7.64 (3H, m), 8.51-8.54 (1H, app-dd, J=1.9 Hz, 7.8 Hz),8.56-8.58 (1H, app-dd, J=1.9 Hz, 4.9 Hz)

Synthetic Example 174-hydroxy-3-[1-oxo-2-(2-thienyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using 2-thienylacetylchloride in place of 3-methoxyphenylacetyl chloride to obtain4-hydroxy-3-[1-oxo-2-(2-thienyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(26%), mp 197-199° C.

¹H NMR (CDCl₃) δ:4.86 (2H, s), 6.98-7.01 (2H, m), 7.19-7.30 (4H, m),7.50-7.64 (3H, m), 8.51-8.54 (1H, app-dd, J=2.0 Hz, 7.9 Hz), 8.56-8.58(1H, app-dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 184-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-nitrophenylacetyl chloride in place of 3-methoxyphenylacetyl chlorideto obtain4-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(20%), mp 223-227° C.

¹H NMR (CDCl₃) δ:4.74 (2H, s), 7.21-7.26 (1H, dd, J=4.6 Hz, 7.9 Hz),7.26-7.29 (2H, m), 7.44-7.49 (2H, app-d, J=8.6 Hz), 7.49-7.65 (3H, m),8.17-8.22 (2H, app-d, J=8.9 Hz), 8.52-8.55 (1H, dd, J=2.0 Hz, 7.9 Hz),8.57-8.60 (1H, dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 194-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using3-nitrophenylacetyl chloride in place of 3-methoxyphenylacetyl chlorideto obtain4-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(37%), mp 157-161° C.

¹H NMR (CDCl₃) δ:4.75 (2H, s), 7.21-7.26 (1H, dd, J=4.6 Hz, 7.9 Hz),7.26-7.40 (2H, m), 7.48-7.67 (5H, m), 8.13-8.17 (2H, m), 8.52-8.55 (1H,dd, J=1.7 Hz, 7.9 Hz), 8.58-8.60 (1H, dd, J=1.7 Hz, 4.6 Hz)

Synthetic Example 204-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using2-nitrophenylacetyl chloride in place of 3-methoxyphenylacetyl chlorideto obtain4-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(41%), mp 194-195° C.

¹H NMR (CDCl₃) δ: 5.02 (2H, s), 7.21-7.25 (1H, dd, J=4.6 Hz, 7.9 Hz),7.30-7.34 (3H, m), 7.47-7.66 (5H, m), 8.16-8.20 (1H, dd, J=1.3 Hz, 8.2Hz), 8.51-8.54 (1H, dd, J=2.0 Hz, 7.9 Hz), 8.58-8.60 (1H, dd, J=2.0 Hz,4.6 Hz)

Synthetic Example 214-hydroxy-3-[1-oxo-2-(2,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using2,5-dimethoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(2,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(56%), mp 159-161° C.

¹H NMR (CDCl₃) δ:3.74 (3H, s), 3.77 (3H, s), 4.58 (2H, s), 6.71-6.84(3H, m), 7.19-7.24 (1H, app-dd, J=4.6 Hz, 7.9 Hz), 7.27-7.33 (2H, m),7.49-7.64 (3H, m), 8.51-8.54 (1H, app-dd, J=2.0 Hz, 7.9 Hz), 8.56-8.59(1H, app-dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 224-hydroxy-3-[1-oxo-2-(3,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using3,4-dimethoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(3,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(52%), mp 161-163° C.

¹H NMR (CDCl₃) δ:3.86 (3H, s), 3.87 (3H, s), 4.58 (2H, s), 6.85 (3H,app-s), 7.19-7.23 (1H, app-dd, J=4.6 Hz, 7.6 Hz), 7.25-7.29 (2H, m),7.50-7.65 (3H, m), 8.50-8.57 (2H, m)

Synthetic Example 234-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using3,5-dimethoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(35%), mp 169.5-171° C.

¹H NMR (CDCl₃) δ:3.77 (6H, s), 4.58 (2H, s), 6.38-6.40 (1H, app-t, J=2.3Hz), 6.45-6.46 (2H, app-d, J=2.3 Hz), 7.19-7.24 (1H, app-dd, J=4.6 Hz,7.9 Hz), 7.25-7.30 (3H, m), 7.52-7.63 (3H, m), 8.50-8.54 (1H, app-dd,J=2.0 Hz, 7.9 Hz), 8.55-8.58 (1H, app-dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 244-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using2,4-dimethoxyphenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(19%), mp 200-202° C.

¹H NMR (CDCl₃) δ:3.76 (3H, s), 3.82 (3H, s), 4.54 (2H, s), 6.46-6.50(2H, m), 7.01-7.04 (1H, app-d, J=7.2 Hz), 7.18-7.23 (1H, app-dd, J=4.6Hz, 7.2 Hz), 7.27-7.33 (2H, m), 7.49-7.63 (3H, m), 8.50-8.54 (1H,app-dd, J=2.0 Hz, 7.9 Hz), 8.55-8.58 (1H, app-dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 254-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-cyanophenylacetyl chloride in place of 3-methoxyphenylacetyl chlorideto obtain4-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(18%), mp 227-230° C.

¹H NMR (CDCl₃) δ:4.69 (2H, s), 7.21-7.25 (1H, dd, J=4.6 Hz, 7.9 Hz),7.25-7.29 (2H, m), 7.39-7.42 (2H, app-d, J=8.2 Hz), 7.50-7.68 (3H, m),7.61-7.64 (2H, app-d, J=8.2 Hz), 8.51-8.55 (1H, dd, J=2.0 Hz, 7.9 Hz),8.57-8.59 (1H, dd, J=1.6 Hz, 4.6 Hz)

Synthetic Example 264-hydroxy-3-[1-oxo-2-(4-ethoxycarbonylmethylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-ethoxycarbonylmethylphenylacetyl chloride in place of3-methoxyphenylacetyl chloride to obtain4-hydroxy-3-[1-oxo-2-(4-ethoxycarbonylmethylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(22%), mp 156-158° C.

¹H NMR(CDCl₃) δ:1.25 (3H, t, J=7.3 Hz), 3.60 (2H, s), 4.14 (2H, q, J=7.3Hz), 4.62 (2H, s), 7.18-7.23 (1H, dd, J=4.6 Hz, 7.9 Hz), 7.26-7.29 (6H,m), 7.49-7.64 (3H, m), 8.50-8.53 (1H, dd, J=2.0 Hz, 7.9 Hz), 8.55-8.57(1H, dd, J=2.0 Hz, 4.9 Hz)

Synthetic Example 274-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-fluorophenylacetyl chloride in place of 3-methoxyphenylacetyl chlorideto obtain4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(43%), mp 185-187° C.

¹H NMR (CDCl₃) δ:4.61 (2H, s), 6.70-7.62 (2H, app-t, J=8.6 Hz),7.19-7.28 (5H, m), 7.52-7.65 (3H, m), 8.51-8.57 (2H, m)

Synthetic Example 284-hydroxy-3-[1-oxo-2-(4-methylthiophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 14 was repeated using4-methylthiophenylacetyl chloride in place of 3-methoxyphenylacetylchloride to obtain4-hydroxy-3-[1-oxo-2-(4-methylthiophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(49%), mp 177-182° C.

¹H NMR (CDCl₃) δ:2.47 (3H, s), 4.60 (2H, s), 7.19-7.29 (7H, m),7.49-7.64 (3H, m), 8.50-8.53 (1H, dd, J=2.0 Hz, 7.9 Hz), 8.55-8.58 (1H,dd, J=2.0 Hz, 4.6 Hz)

Synthetic Example 291-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2(1H)-one

(1) To methyl 2-(3-cyanophenylamino)nicotinate (507 mg, 2.0 mmol;synthesized according to WO, A, 01/42244) was added DMF (2 ml) and butylacetate (2 ml) to form a solution at 80° C. To the solution was addedpotassium t-butoxide (449 mg, 4.0 mmol), and the mixture was stirred atabout 130° C. overnight, evaporated while heating, and allowed to standuntil it was cooled. The resulting residue was dissolved in water,partitioned with xylene, and washed. The resultant aqueous layer wasacidified with hydrochloric acid, and filtered off to give precipitateswhich were washed with water and dried to afford a mixture containing1-(3-cyanophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one (321 mg, 61%).

mp 287-288 (dec.) ° C.

¹H NMR (DMSO-d₆) δ:5.94 (1H, s), 7.30 (1H, dd, J=4.8 Hz, 7.9 Hz), 7.64(1H, dt, J=8.1 Hz, 1.5 Hz), 7.71 (1H, t, J=8.1 Hz), 7.84-7.86 (1H, m),7.91 (1H, dt, J=7.4 Hz, 1.5 Hz), 8.29 (1H, dd, J=1.8 Hz, 7.7 Hz), 8.42(1H, dd, J=1.8 Hz, 4.8 Hz)

(2) To a suspension of a mixture containing1-(3-cyanophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one (958 mg, 3.64mmol) in DMF (16 ml) was added sodium hydride (about 60%, 350 mg, 8.74mmol, 2.4 eq.), and the mixture was stirred until the production ofhydrogen was completed. Next, after phenylacetyl chloride (563 mg, 3.64mmol, 1.0 eq.) was added, the mixture was stirred at room temperature,admixed with water, acidified with hydrochloric acid, filtered off togive precipitates which were washed with water. The resultant residuewas purified by flash column chromatography to afford1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2(1H)-one(341 mg, 25%).

mp 216-218° C.

¹H NMR (CDCl₃) δ: 4.60 (2H, s), 7.23-7.35 (6H, m), 7.52-7.60 (2H, m),7.70 (1H, t, J=7.9 Hz), 7.80 (1H, dt, J=7.9 Hz, 1.3 Hz), 8.50-8.52 (1H,m), 8.54 (1H, dd, J=2.0 Hz, 5.6 Hz)

Synthetic Example 304-hydroxy-3-(1-oxo-4-phenylbutyl)-1-phenyl-1,8-naphthyridin-2(1H)-one

The procedure of Synthetic Example 5 was repeated using phenylbutylylchloride in place of phenylacetyl chloride to afford4-hydroxy-3-(1-oxo-4-phenylbutyl)-1-phenyl-1,8-naphthyridin-2(1H)-one(yield for 2 steps: 49%).

mp 200.5-201.5° C.

¹H NMR (CDCl₃) δ:1.99-2.10 (2H, m), 2.66-2.72 (2H, m), 3.34 (2H, t,J=7.6 Hz), 7.12-7.29 (8H, m), 7.47-7.62 (3H, m), 8.52 (1H, dd, J=2.0 Hz,7.9 Hz), 8.55 (1H, dd, J=2.0 Hz, 4.9 Hz)

Synthetic Example 311-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one

(1) To a solution of methyl 2-(3-fluorophenylamino)-nicotinate (4.90 g,16.2 mmol; synthesized according to WO, A, 01/42244) in1,2-dichloroethane (80 ml) was added at 80° C. trichloromethylchloroformate (also called: diphosgene, 5.9 ml, 48.3 mmol) graduallydropwise over about 30 minutes. Three hours later, activated carbon (130mg) was added, and the mixture was heated under reflux for 30 minutes,filtered off, and then evaporated. The resultant residue was washed withisopropyl ether, and dried to give1-(3-fluorophenyl)-2H-pyrido[2,3-d][3,1]oxazin-2,4(1H)-dione (3.42 g,82%) as crystals.

mp 164-166° C.

¹H NMR (CDCl₃) δ:7.07-7.12 (1H, app-td, J=8.4 Hz, 2.0 Hz), 7.14-7.17(1H, m), 7.22-7.28 (1H, m), 7.29-7.33 (1H, app-dd, J=4.8 Hz, 7.7 Hz),7.51-7.59 (1H, app-dt, J=6.1 Hz, 8.4 Hz), 8.47-8.51 (1H, app-dd, J=2.0Hz, 7.7 Hz), 8.58-8.60 (1H, app-dd, J=2.0 Hz, 4.9 Hz)

(2) To a solution of diethyl malonate (1.50 g, 9.30 mmol) indimethylacetamide (14 ml) was added sodium hydride (about 60%, 467 mg,11.65 mmol), and the mixture was stirred to form a solution until theproduction of hydrogen was completed. To the resulting solution wasadded 1-(3-fluorophenyl)-2H-pyrido[2,3-d][3,1]oxazin-2,4(1H)-dione (2.36g, 9.15 mmol) while ice-cooling, and the mixture was stirred at 150° C.for 1 hour, cooled to room temperature, treated with ethyl acetate,allowed to stand. The resultant precipitate was collected by filtration,and washed with ethyl acetate, filtered off to give a residue which wasdissolved in water, acidified to pH1 with hydrochloric acid to formprecipitates. The resultant precipitate was collected by filtration,washed with water, and dried to afford3-ethoxycarbonyl-1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2 (1H)(2.66 g, 88%) as crystals.

mp 187-189° C.

¹H NMR (CDCl₃) δ: 1.44 (3H, t, J=7.1 Hz), 4.48 (2H, q, J=7.1 Hz),6.97-7.02 (1H, m), 7.03-7.07 (1H, app-dq, J=7.7 Hz, 1.0 Hz), 7.14-7.24(2H, m), 7.46-7.55 (1H, m), 8.47-8.50 (1H, app-dd, J=2.0 Hz, 7.9 Hz),8.54-8.56 (1H, app-dd, J=2.0 Hz, 4.6 Hz), 14.47 (1H, s)

(3) To3-ethoxycarbonyl-1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one(328 mg, 1.0 mmol) was added an aqueous solution (7 ml) of potassiumhydroxide (560 mg, 10.0 mmol), and the mixture was heated under refluxovernight, acidified to pH1 with conc. hydrochloric acid, refluxed for 1hour, filtered off to give precipitates which were washed with water anddried to afford 1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one(194.5 mg, 76%) as crystals.

mp 272° C. (dec.)

¹H NMR (DMSO-d₆) δ: 5.94 (1H, s), 7.06-7.10 (1H, m), 7.16-7.21 (1H,app-dt, J=9.9 Hz, 1.8 Hz), 7.24-7.31 (2H, m), 7.48-7.57 (1H, m),8.25-8.29 (1H, app-dd, J=1.8 Hz, 7.9 Hz), 8.41-8.43 (1H, app-dd, J=1.8Hz, 7.9 Hz), 11.91 (1H, s)

Examples

Disclosed herein below are examples which are merely illustrative of thepresent invention and should not be construed as limiting the scope ofthe invention. It should be noted that the present invention encompassesvarious embodiments.

Example 15-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(50 mg, 0.13 mmol, prepared in Synthetic Example 1) in ethanol (1 ml)was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.) and theresultant mixture was heated under reflux overnight. The liquid reactionmixture was cooled to room temperature, and then filtered to giveprecipitates which were dried to obtain5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(40 mg, 81%).

mp 267-269° C.

¹H NMR (DMSO-d₆) δ:3.06-3.12 (2H, m), 3.26-3.33 (2H, m), 7.23-7.29 (4H,m), 7.31-7.36 (1H, app-dd, J=4.6 Hz, 7.6 Hz), 7.41-7.56 (3H, m),8.35-8.38 (1H, app-dd, J=1.3 Hz, 4.3 Hz), 8.43-8.45 (2H, app-d, J=5.9Hz), 8.47-8.51 (1H, app-dd, J=1.7 Hz, 7.6 Hz), approximately 14 (1H,brs)

Example 21-methyl-5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo-[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(100 mg, 0.27 mmol, prepared in Synthetic Example 1) in ethanol (2 ml)was added methylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the mixturewas stirred at room temperature to form a solution which was thenstirred for 30 minutes. After it was perceived that precipitationstarted, the mixture was heated under reflux for 3 hours and cooled toroom temperature. Next, to the liquid mixture was added additionalmethylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the resultant mixturewas heated overnight with stirring at 70° C. The liquid reaction mixturewas cooled to room temperature, and then filtered to give precipitateswhich were dried to obtain1-methyl-5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(94 mg, 92%).

mp 285-286° C.

¹H NMR (CDCl₃) δ: 3.11-3.17 (2H, m), 3.35-3.41 (2H, m), 4.36 (3H, s),7.21-7.31 (5H, m), 7.48-7.65 (3H, m), 8.36-8.40 (1H, app-dd, J=1.7 Hz,7.9 Hz), 8.44-8.48 (3H, m)

Example 35-phenyl-3-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

The procedure of Example 1 was repeated using a suspension of4-hydroxy-3-[1-oxo-3-(pyridin-3-yl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(50 mg, 0.14 mmol, prepared in Synthetic Example 2) in ethanol (10 ml),and hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.), to obtain5-phenyl-3-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(yield: 78%).

mp 322° C. (dec.)

¹H NMR (DMSO-d₆) δ:3.08 (2H, t, J=8.3 Hz), 7.27-7.36 (4H, m), 7.44-7.55(3H, m), 7.61-7.64 (1H, app-d, J=7.6 Hz), 8.36-8.41 (3H, m), 8.47-8.51(1H, app-dd, J=1.7 Hz, 7.6 Hz)

Example 45-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

The procedure of Example 1 was repeated using a suspension of4-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(16 mg, 0.045 mmol, prepared in Synthetic Example 3) in ethanol (5 ml),and hydrazine monohydrate (80%, 10 μl, 0.25 mmol, 5.5 eq.) to obtain5-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(yield: 76%).

mp 306° C. (dec.)

¹H NMR (DMSO-d₆) δ:4.38 (2H, s), 7.24-7.54 (7H, m), 7.70-7.73 (1H, m),8.36-8.38 (1H, app-dd, J=1.7 Hz, 5.0 Hz), 8.40-8.42 (1H, m), 8.49-8.52(1H, app-dd, J=1.7 Hz, 7.6H), 8.56-8.57 (1H, app-d, J=2.3 Hz)

Example 55-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(100 mg, 0.27 mmol, prepared in Example 1) in chloroform (80 ml) wasadded a solution of m-chloroperbenzoic acid (mCPBA, 70%, 67 mg, 0.27mmol, 1.0 eq.) in chloroform (1 ml) at room temperature, and the mixturewas stirred. One hour later, an additional solution of mCPBA (70%, 31mg, 0.13 mmol, 0.5 eq.) in chloroform (1 ml) was added, and the mixturewas stirred for additional 2 hours. To the resultant liquid reactionmixture was added saturated aqueous sodium hydrogen carbonate and themixture was stirred, then filtered to give precipitates which weresubjected to recrystallization with DMF, and dried to give5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(58 mg, 55%).

mp 285° C. (dec.)/DMF

¹H NMR (DMSO-d₆) δ:3.02-3.07 (2H, m), 3.20-3.26 (2H, m), 7.22-7.27 (5H,m), 7.38-7.54 (3H, m), 8.06-8.08 (2H, app-d, J=6.9 Hz), 8.25-8.27 (1H,app-dd, J=1.7 Hz, 4.6 Hz), 8.46-8.50 (1H, app-dd, J=2.0 Hz, 7.6 Hz)

Example 65-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one(416 mg, 1.0 mmol, prepared in Synthetic Example 4) in ethanol (15 ml)was added hydrazine monohydrate (80%, 180 μl, 4.5 mmol, 4.5 eq.), andthe resultant mixture was treated in the same manner as in Example 1 togive5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(394 mg, 96%).

mp 161-165° C.

¹H NMR (DMSO-d₆) δ:3.06-3.12 (2H, m), 3.27-3.30 (2H, m), 7.24-7.26 (2H,app-dd, J=1.7 Hz, 4.6 Hz), 7.35-7.39 (1H, app-dd, J=4.9 Hz, 7.9 Hz),7.83-7.85 (2H, m), 8.28-8.38 (3H, m), 8.43-8.45 (2H, app-dd, J=1.7 Hz,4.3 Hz), 8.50-8.53 (1H, app-dd, J=2.0 Hz, 7.9 Hz)

Example 75-(3-nitrophenyl)-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(300 mg, 0.73 mmol, prepared in Example 6) was added chloroform (250ml), and mixture was heated to form a solution. After it was perceivedthat the mixture was a solution when cooled to room temperature, asolution of mCPBA (about 70%, 269 mg, 1.09 mmol, 1.5 eq.) in chloroform(3 ml) was added dropwise. One hour later, an additional solution ofmCPBA (about 70%, 90 mg, 0.37 mmol, 0.5 eq.) in chloroform (1 ml) wasadded and the mixture was stirred for 1.5 hours. To the resultingreaction suspension was added saturated aqueous sodium hydrogencarbonate and it was stirred, and filtered off to remove insolubles. Theprecipitates were washed with DMF under heating, filtered off, and driedto give5-(3-nitrophenyl)-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(283 mg, 91%).

mp 328° C. (dec.)

¹H NMR (DMSO-d₆) δ:3.06 (2H, t, J=7.6 Hz), 3.27 (2H, t, J=7.6 Hz),7.22-7.24 (2H, app-d, J=6.9 Hz), 7.35-7.40 (1H, app-dd, J=5.3 Hz, 7.6Hz), 7.80-7.87 (2H, m), 8.07-8.10 (2H, app-d, J=6.9 Hz), 8.28-8.38 (3H,m), 8.50-8.53 (2H, app-dd, J=2.0 Hz, 7.9 Hz), 14.04 (1H, br)

Example 85-(3-aminophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(150 mg, 0.36 mmol, prepared in Example 6) in conc. hydrochloric acid (3ml) was added tin chloride.2H₂O (450 mg, 3-fold weights) and the mixturewas stirred overnight, then treated with saturated aqueous sodiumhydrogen carbonate to make it to pH8-9, and extracted with chloroform 4times. The resulting organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, and evaporatedto give a residue (about 110 mg). The residue was recrystallized fromDMF to afford5-(3-aminophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(16.3 mg, 12%).

mp 261-263° C./DMF

¹H NMR (DMSO-d₆) δ:3.06-3.12 (2H, m), 3.26-3.29 (2H, m), 5.18 (2H, brs),6.34-6.38 (1H, m), 6.39-6.41 (1H, app-t, J=2.0 Hz), 6.61-6.65 (1H, m),7.10-7.16 (1H, app-t, J=7.9 Hz), 7.24-7.26 (2H, app-d, J=5.9 Hz),7.30-7.34 (1H, app-dd, J=4.6 Hz, 7.6 Hz), 8.39-8.48 (4H, m), 13.97 (1H,br)

Example 93-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2(1H)-one(2.33 g, 6.54 mmol, prepared in Synthetic Example 5) in DMF (50 ml) wasadded hydrazine monohydrate (80%, 970 μl, 24.21 mmol, 3.7 eq.) and themixture was then stirred at 100 to 110° C. for 4 hours, admixed withwater to precipitate crystals, and allowed to stand until it was cooled.Next, the cooled mixture was filtered, washed with water, and dried togive 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(1.90 g, 82%).

mp 305-308° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.36 (2H, s), 7.15-7.36 (8H, m), 7.40-7.55 (3H, m),8.35 (1H, dd, J=1.7 Hz, 4.6 Hz), 8.50 (1H, dd, J=1.6 Hz, 7.6 Hz)

Example 105-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one(110 mg, 0.30 mmol, prepared in Synthetic Example 6) in ethanol (6 ml)was added hydrazine monohydrate (80%, 44 μl, 1.1 mmol, 3.7 eq.), and themixture was treated in the same manner as in Example 1 to give5-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(80 mg, 73%).

mp 248-250° C.

¹H NMR (DMSO-d₆) δ:3.02-3.08 (2H, m), 3.23-3.29 (2H, m), 7.14-7.35 (8H,m), 7.41-7.56 (3H, m), 8.36 (1H, dd, J=2.0 Hz, 4.6 Hz), 8.49 (1H, dd,J=1.6 Hz, 7.6 Hz), 14 (1H, br)

Example 113-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(104 mg, 0.25 mmol, prepared in Synthetic Example 7) in DMF (2 ml) wasadded hydrazine monohydrate (80%, 40 μl, 1.0 mmol, 4.0 eq.), and themixture was treated in the same manner as in Example 9 to give3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(100 mg, 97%).

mp 260-262° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.17-3.03 (4H, m), 7.25-7.29 (2H, m), 7.34 (1H, dd,J=4.6 Hz, 7.6 Hz), 7.41-7.56 (3H, m), 7.49-7.52 (2H, app-d, J=8.9 Hz),8.12-8.16 (2H, app-d, J=8.6 Hz), 8.37 (1H, dd, J=1.7 Hz, 4.6 Hz), 8.49(1H, dd, J=1.7 Hz, 7.6 Hz), 14 (1H, br)

Example 123-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(270 mg, 0.69 mmol, prepared in Synthetic Example 8) in DMF (5 ml) wasadded hydrazine monohydrate (80%, 102 μl, 2.55 mmol, 3.7 eq.), and themixture was treated in the same manner as in Example 9 to give3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(243 mg, 90%).

mp 267-269° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.12-3.18 (2H, m), 3.25-3.32 (2H, m), 7.25-7.29 (2H,m), 7.33 (1H, dd, J=4.6 Hz, 7.6 Hz), 7.41-7.44 (2H, app-d, J=8.3 Hz),7.41-7.56 (3H, m), 7.72-7.75 (2H, app-d, J=8.3 Hz), 8.37 (1H, dd, J=1.3Hz, 4.6 Hz), 8.50 (1H, dd, J=1.6 Hz, 7.6 Hz), 14 (1H, br)

Example 133-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(131 mg, 0.32 mmol, prepared in Example 11) in DMF (4 ml) and methanol(4 ml) was added activated carbon-palladium (13 mg), and the mixture wasstirred under hydrogen atmosphere for 3.5 hours, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(113 mg, 93%).

mp>310° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:2.82-2.89 (2H, m), 3.17 (2H, br), 4.84 (2H, brs),6.45-6.48 (2H, app-d, J=8.2 Hz), 6.86-6.89 (2H, app-d, J=7.9 Hz),7.25-7.29 (3H, m), 7.41-7.56 (3H, m), 8.35 (1H, br), 8.48 (1H, dd, J=1.3Hz, 7.6 Hz), 14 (1H, br)

Example 143-[2-(4-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(100 mg, 0.26 mmol, prepared in Example 12) in DMSO (2 ml) was added 50%sulfuric acid (2 ml) and the mixture was heated under reflux for 2hours. To the resultant reaction mixture was added water, andprecipitates were filtered off, and dried to give3-[2-(4-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(107 mg, quantitative yield).

mp 318-320° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.10-3.31 (4H, m), 7.26-7.55 (8H, m), 7.83-7.86 (2H,app-d, J=8.2 Hz), 8.36 (1H, br), 8.49 (1H, d, J=6.9 Hz), 12.82 (1H, br),14 (1H, br)

Example 153-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(415 mg, 1.0 mmol, prepared in Synthetic Example 9) in DMF (10 ml) wasadded hydrazine monohydrate (80%, 160 μl, 3.99 mmol, 4.0 eq.), and themixture was then stirred at 100 to 110° C. for 7 hours. The reactionmixture was admixed with water to precipitate crystals, allowed to standuntil it was cooled, filtered off, washed with water, and dried to give3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(389 mg, 94%).

mp 245-247° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.22-3.33 (4H, m), 7.26-7.28 (2H, m), 7.31-7.36 (1H,app-dd, J=4.6, 7.6 Hz), 7.44-7.59 (4H, m), 7.67-7.70 (1H, app-d, J=7.6Hz), 8.05-8.10 (2H, m), 8.35-8.38 (1H, m), 8.47-8.50 (1H, app-dd, J=2.0Hz, 7.6 Hz), 14.01 (1H, s)

Example 163-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(837 mg, 2.0 mmol, prepared in Synthetic Example 10) in DMF (20 ml) wasadded hydrazine monohydrate (80%, 350 μl, 8.74 mmol, 4.4 eq.), and themixture was then stirred at 100 to 110° C. overnight. The reactionmixture was admixed with water to precipitate crystals, allowed to standuntil it was cooled, filtered off, washed with water, and dried to give3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(790 mg, 95%).

mp 333-335° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.32 (4H, m), 7.25-7.28 (2H, m), 7.31-7.36 (1H,app-dd, J=4.6, 7.6 Hz), 7.44-7.62 (6H, m), 7.90-7.93 (1H, m), 8.36-8.37(1H, m), 8.47-8.51 (1H, app-dd, J=2.0 Hz, 7.6 Hz), 14.01 (1H, s)

Example 173-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(991 mg, 2.51 mmol, prepared in Synthetic Example 11) in DMF (25 ml) wasadded hydrazine monohydrate (80%, 371 μl, 9.26 mmol, 3.7 eq.), and themixture was treated in the same manner as in Example 16 to give3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(953 mg, 97%).

mp 315.5-316.5° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.2-3.5 (4H, m), 7.24-7.27 (2H, app-d, J=7.9 Hz),7.31-7.63 (7H, m), 7.73-7.75 (1H, d, J=7.6 Hz), 8.36-8.38 (1H, m),8.46-8.50 (1H, m)

Example 183-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(495 mg, 1.25 mmol, prepared in Synthetic Example 12) in DMF (12 ml) wasadded hydrazine monohydrate (80%, 148 μl, 3.69 mmol, 3.0 eq.), and themixture was treated in the same manner as in Example 16 to give3-[(2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(456 mg, 93%).

mp 219.5-224.5° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.10-3.15 (2H, m), 3.26-3.29 (2H, m), 7.26-7.29 (2H,m), 7.31-7.36 (1H, dd, J=4.9 Hz, 7.6 Hz), 7.41-7.58 (5H, m), 7.64-7.70(2H, m), 8.35-8.38 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.47-8.51 (1H, dd, J=1.7Hz, 7.9 Hz), approximately 14 (1H, br)

Example 193-[2-(4-methylphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-3-(4-methylphenyl)propyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(362 mg, 0.94 mmol, prepared in Synthetic Example 13) in DMF (10 ml) wasadded hydrazine monohydrate (80%, 150 μl, 3.74 mmol, 4.0 eq.), and themixture was then stirred at 100 to 130° C. for 2 hours. The reactionmixture was admixed with water to precipitate crystals, allowed to standuntil it was cooled, filtered off, washed with water, and dried to give3-[2-(4-methylphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(335 mg, 94%).

mp 264-265° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:2.25 (3H, s), 2.99 (2H, t, J=8.6 Hz), 3.23 (1H, t,J=8.6 Hz), 7.06-7.13 (4H, m), 7.26-7.35 (3H, m), 7.42-7.55 (3H, m),8.35-8.37 (1H, m), 8.47-8.51 (1H, app-dd, J=1.7 Hz, 7.6 Hz), 13.98 (1H,s)

Example 203-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(3-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(50 mg, 0.13 mmol, prepared in Synthetic Example 14) in DMF (1 ml) wasadded hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.8 eq.), and themixture was treated in the same manner as in Example 16 to give3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(41 mg, 83%).

mp 234-236° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.69 (3H, s), 4.32 (2H, s), 6.75-6.78 (1H, app-d,J=7.8 Hz), 6.88-6.93 (2H, m), 7.16-7.21 (1H, app-t, J=7.9 Hz), 7.25-7.27(2H, m), 7.30-7.35 (1H, app-dd, J=5.0 Hz, 7.9 Hz), 7.44-7.54 (3H, m),8.35-8.36 (1H, m), 8.48-8.51 (1H, app-dd, J=2.0 Hz, 7.9 Hz)

Example 213-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(50 mg, 0.13 mmol, prepared in Synthetic Example 15) in DMF (1 ml) wasadded hydrazine monohydrate (80%, 1 ml, 24.96 mmol, 192 eq.), and themixture was treated in the same manner as in Example 16 to give3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(44 mg, 89%).

mp 300-302° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.69 (3H, s), 4.28 (2H, s), 6.81-6.85 (2H, app-d,J=8.6 Hz), 7.24-7.27 (4H, app-d, J=8.6 Hz), 7.29-7.34 (1H, app-dd, J=5.0Hz, 7.9 Hz), 7.41-7.54 (3H, m), 8.33-8.36 (1H, app-dd, J=1.7 Hz, 5.0Hz), 8.47-8.51 (1H, app-dd, J=1.7 Hz, 7.9 Hz)

Example 223-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(2-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(121 mg, 0.31 mmol, prepared in Synthetic Example 16) in DMF (3 ml) wasadded hydrazine monohydrate (80%, 50 μl, 1.25 mmol, 4.0 eq.), and themixture was treated in the same manner as in Example 16 to give3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(111 mg, 93%).

mp 276-277° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.80 (3H, s), 4.31 (2H, s), 6.78-6.85 (1H, m),6.96-7.03 (2H, m), 7.14-7.34 (4H, m), 7.42-7.53 (3H, m), 8.33-8.35 (1H,app-dd, J=1.4 Hz, 4.6 Hz), 8.49-8.52 (1H, app-dd, J=1.4 Hz, 7.6 Hz)

Example 233-(2-thienylmethyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(2-thienyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(30 mg, 0.08 mmol, prepared in Synthetic Example 17) in DMF (1.5 ml) wasadded hydrazine monohydrate (80%, 30 μl, 0.75 mmol, 9.4 eq.), and themixture was treated in the same manner as in Example 16 to give3-(2-thienylmethyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(22 mg, 72%).

mp 282-284° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.53 (3H, s), 6.90-6.99 (2H, m), 7.25-7.55 (7H, m),8.39-8.52 (2H, m), 14.18 (1H, s)

Example 243-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(304 mg, 0.76 mmol, prepared in Synthetic Example 18) in DMF (7.5 ml)was added hydrazine monohydrate (80%, 108 μl, 2.70 mmol, 3.6 eq.), andthe mixture was then stirred at 100 to 110° C. for 5 hours. The reactionmixture was admixed with water to precipitate crystals, allowed to standuntil it was cooled, filtered off, washed with water, and dried to give3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(260 mg, 86%).

mp 254-255° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ: 4.49 (2H, s), 7.24-7.27 (2H, app-d, J=8.2 Hz),7.33-7.37 (1H, dd, J=4.6 Hz, 7.9 Hz), 7.40-7.54 (5H, m), 7.57-7.60 (2H,app-d, J=8.2 Hz), 8.14-8.17 (2H, app-d, J=7.9 Hz), 8.37-8.38 (1H, d,J=4.9 Hz), 8.50-8.52 (1H, dd, J=7.6 Hz)

Example 253-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(568 mg, 1.42 mmol, prepared in Synthetic Example 19) in DMF (14 ml) wasadded hydrazine monohydrate (80%, 203 μl, 5.07 mmol, 3.6 eq.), and themixture was treated in the same manner as in Example 24 to give3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(397 mg, 71%).

mp>320° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.51 (2H, s), 7.25-7.28 (2H, m), 7.33-7.37 (1H, dd,J=4.6 Hz, 7.6 Hz), 7.41-7.63 (4H, m), 7.79-7.81 (1H, d, J=7.9 Hz),8.06-8.10 (1H, m), 8.20 (1H, s), 8.37-8.39 (1H, dd, J=2.0 Hz, 4.9 Hz),8.49-8.53 (1H, dd, J=2.0 Hz, 7.9 Hz), approximately 14.2 (1H, br)

Example 263-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(643 mg, 1.60 mmol, prepared in Synthetic Example 20) in DMF (16 ml) wasadded hydrazine monohydrate (80%, 230 μl, 5.74 mmol, 3.6 eq.), and themixture was treated in the same manner as in Example 24 to give3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(541 mg, 85%).

mp 318-320° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.69 (2H, s), 7.25-7.28 (2H, m), 7.34-7.38 (1H, dd,J=4.6 Hz, 7.6 Hz), 7.43-7.55 (5H, m), 7.63-7.68 (1H, td, J=7.6 Hz, 1.3Hz), 7.99-8.02 (1H, dd, J=1.3 Hz, 8.2 Hz), 8.38-8.40 (1H, dd, J=1.7 Hz,4.6 Hz), 8.47-8.51 (1H, dd, J=1.7 Hz, 7.6 Hz), approximately 14 (1H, br)

Example 273-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(2,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(200 mg, 0.48 mmol, prepared in Synthetic Example 21) in DMF (5 ml) wasadded hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and themixture was treated in the same manner as in Example 16 to give3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(162 mg, 82%).

mp 248-250° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.61 (3H, s), 3.75 (3H, s), 4.29 (2H, s), 6.64-6.66(1H, app-d, J=3.0 Hz), 6.73-6.78 (1H, app-dd, J=3.0 Hz, 8.9 Hz),6.88-6.91 (1H, app-d, J=8.9 Hz), 7.24-7.54 (6H, m), 8.35-8.37 (1H, m),8.49-8.52 (1H, app-dd, J=1.6 Hz, 7.6 Hz), 13.98 (1H, s)

Example 283-(3,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(3,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(200 mg, 0.48 mmol, prepared in Synthetic Example 22) in DMF (5 ml) wasadded hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and themixture was treated in the same manner as in Example 16 to give3-(3,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(159 mg, 80%).

mp 230-232° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.68 (6H, s), 4.28 (2H, s), 6.83 (2H, app-s), 7.03(1H, app-s), 7.25-7.55 (6H, m), 8.34-8.35 (1H, m), 8.48-8.50 (1H, m),14.08 (1H, s)

Example 293-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(200 mg, 0.48 mmol, prepared in Synthetic Example 23) in DMF (5 ml) wasadded hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and themixture was treated in the same manner as in Example 16 to give3-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(179 mg, 90%).

mp 258-259° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.68 (6H, s), 4.27 (2H, s), 6.31-6.35 (2H, m),6.51-6.52 (2H, app-d, J=2.0 Hz), 7.25-7.53 (6H, m), 8.34-8.36 (1H, m),8.48-8.51 (1H, m)

Example 303-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(100 mg, 0.24 mmol, prepared in Synthetic Example 24) in DMF (2 ml) wasadded hydrazine monohydrate (80%, 50 μl, 1.25 mmol, 5.2 eq.), and themixture was treated in the same manner as in Example 24 to give3-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(87 mg, 87%).

mp 266-267° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.72 (3H, s), 3.78 (3H, s), 4.23 (2H, s), 6.39-6.43(1H, app-dd, J=2.3 Hz, 8.3 Hz), 6.53-6.54 (1H, app-d, J=2.3 Hz),6.95-6.98 (1H, app-d, J=8.3 Hz), 7.24-7.27 (2H, m), 7.29-7.34 (1H,app-dd, J=4.6 Hz, 7.6 Hz), 7.40-7.54 (3H, m), 8.34-8.35 (1H, m),8.48-8.51 (1H, app-dd, J=1.7 Hz, 7.6 Hz)

Example 313-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(265 mg, 0.69 mmol, prepared in Synthetic Example 25) in DMF (7 ml) wasadded hydrazine monohydrate (80%, 82 μl, 2.05 mmol, 3.0 eq.), and themixture was treated in the same manner as in Example 16 to give3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(190 mg, 73%).

mp 316-318° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.36-4.54 (2H, m), 7.85-7.20 (10H, m), 8.30-8.55 (2H,m), approximately 14.2 (1H, br)

Example 323-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(4-ethoxycarbonylmethylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(128 mg, 0.29 mmol, prepared in Synthetic Example 26) in DMF (3 ml) wasadded hydrazine monohydrate (80%, 34 μl, 0.87 mmol, 3.0 eq.), and themixture was treated in the same manner as in Example 16 to give3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(115 mg, 91%).

mp 263-264° C./DMF-H₂O

¹H NMR (DMSO-d₆, measuring temperature: 80° C.) δ:1.16 (3H, t, J=7.3Hz), 3.56 (2H, s), 4.05 (2H, q, J=7.3 Hz), 4.35 (2H, brs), 7.13-7.53(10H, m), 8.31-8.33 (1H, dd, J=1.3 Hz, 4.6 Hz), 8.46-8.50 (1H, dd, J=1.7Hz, 7.6 Hz), 13.89 (1H, br)

Example 333-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(3.2 g, 8.5 mmol, prepared in Synthetic Example 27) in DMF (50 ml) wasadded hydrazine monohydrate (80%, 1.2 ml, 30 mmol, 3.5 eq.), and themixture was then stirred at 130° C. for 2 hours. The reaction mixturewas admixed with water to precipitate crystals, allowed to stand untilit was cooled, filtered off, washed with water, and dried to give3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(3.1 g, 98%).

mp 271-274° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.34 (2H, s), 7.07-7.13 (2H, m), 7.25-7.55 (8H, m),8.35-8.37 (1H, app-dd, J=2.0 Hz, 5.0 Hz), 8.48-8.51 (1H, app-dd, J=2.0Hz, 7.9 Hz), 14.10 (1H, s)

Example 343-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

(1) To a solution of4-hydroxy-3-[1-oxo-2-(4-methyl-thiophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(201 mg, 0.5 mmol, prepared in Synthetic Example 28) in chloroform (10ml) was added mCPBA (123 mg, 1.0 eq.) while ice-cooling, and the mixturewas stirred for 1 hour. Thereafter, mCPBA (additional total: 285 mg, 1.5eq.) was added, and the mixture was stirred for 1.5 hours, admixed withsaturated aqueous sodium hydrogen carbonate and extracted withchloroform. The organic layer was dried over anhydrous magnesiumsulfate, evaporated, and purified by flash column chromatography toafford4-hydroxy-3-[1-oxo-2-(4-methylsulfonylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(112 mg, 52%).

mp 260-262° C.

¹H NMR (CDCl₃) δ:3.05 (3H, s), 4.73 (2H, s), 7.20-7.25 (1H, dd, J=4.6Hz, 7.6 Hz), 7.25-7.29 (2H, m), 7.48-7.64 (5H, m), 7.88-7.93 (2H, app-d,J=8.6 Hz), 8.51-8.55 (1H, dd, J=2.0 Hz, 7.9 Hz), 8.57-8.59 (1H, dd,J=2.0 Hz, 4.6 Hz)

(2) To a suspension of4-hydroxy-3-[1-oxo-2-(4-methylsulfonylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2(1H)-one(101 mg, 0.23 mmol) in DMF (2.5 ml) was added hydrazine monohydrate(80%, 28 μl, 0.87 mmol, 3.8 eq.), and the mixture was treated in thesame manner as in Example 16 to give3-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(72 mg, 72%).

mp 311.5-312.5° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ: 3.16 (3H, s), 4.47 (2H, s), 7.24-7.28 (2H, m),7.32-7.37 (1H, dd, J=4.6 Hz, 7.6 Hz), 7.40-7.55 (3H, m), 7.57-7.60 (2H,app-d, J=8.2 Hz), 7.82-7.85 (2H, app-d, J=8.6 Hz), 8.36-8.38 (1H, dd,J=1.6 Hz, 4.6 Hz), 8.49-8.53 (1H, dd, J=1.7 Hz, 7.6 Hz), approximately14.2 (1H, br)

Example 353-[2-(3-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(216 mg, 0.52 mmol, prepared in Example 15) in DMF (5 ml) and methanol(5 ml) was added activated carbon-palladium (22 mg), and the mixture wasstirred overnight under hydrogen atmosphere, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-[2-(3-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(189 mg, 94%).

mp 229-231° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:2.86-2.89 (2H, m), 3.18-3.20 (2H, m), 4.96 (2H, s),6.35-6.38 (2H, m), 6.46 (1H, app-s), 6.87-6.93 (1H, app-t, J=7.8 Hz),7.27-7.55 (6H, m), 8.34-8.38 (1H, m), 8.48-8.50 (1H, m), 14.00 (1H, s)

Example 363-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(420 mg, 1.0 mmol, prepared in Example 16) in DMF (45 ml) and methanol(20 ml) was added activated carbon-palladium (45 mg), and the mixturewas stirred overnight under hydrogen atmosphere, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(364 mg, 94%).

mp 289-291° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:2.80-2.89 (2H, m), 3.09-3.15 (2H, m), 5.17 (2H, s),6.44-6.49 (1H, m), 6.56-6.59 (1H, m), 6.88-6.96 (2H, m), 7.29-7.37 (3H,m), 7.42-7.56 (3H, m), 8.37-8.39 (1H, m), 8.50-8.54 (1H, app-dd, J=1.7Hz, 7.6 Hz), 14.02 (1H, s)

Example 373-[2-(2-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(202 mg, 0.52 mmol, prepared in Example 17) in DMSO (20 ml) was added50% sulfuric acid (10 ml), and the mixture was heated under refluxovernight. The resultant reaction mixture was admixed with water, andfiltered to give precipitates which were dried to afford3-[2-(2-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(94 mg, 44%).

mp 302-308° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.28-3.43 (4H, m), 7.26-7.55 (9H, m), 7.79-7.81 (1H,d, J=7.6 Hz), 8.35 (1H, br), 8.48-8.50 (1H, d, J=7.3 Hz), approximately12.9 (1H, br), approximately 13.9 (1H, br)

Example 383-[2-(3-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(300 mg, 0.77 mmol, prepared in Example 18) in DMSO (30 ml) was added50% sulfuric acid (15 ml), and the mixture was heated under refluxovernight. The reaction mixture was admixed with water, and filtered togive precipitates which were dried to afford3-[2-(3-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(87 mg, 28%).

mp 159-161° C./DMF

¹H NMR (DMSO-d₆) δ:3.09-3.15 (2H, m), 3.26-3.29 (2H, m), 7.26-7.56 (8H,m), 7.75-7.78 (1H, d, J=7.3 Hz), 7.82 (1H, s), 8.35-8.37 (1H, d, J=3.6Hz), 8.47-8.51 (1H, dd, J=1.3 Hz, 7.6 Hz), approximately 14 (1H, br)

Example 393-(4-carboxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(180 mg, 0.48 mmol, prepared in Example 31) in DMSO (18 ml) was added50% sulfuric acid (10 ml), and the mixture was stirred at 140° C. Afterwater (5 ml) was added, the mixture was heated under reflux, admixedwith additional water (5 ml), and heated under reflux for totally 3hours. The reaction mixture was admixed with water, and filtered to giveprecipitates which were dried to afford3-(4-carboxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(106 mg, 56%).

mp>320° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.42 (2H, s), 7.25-7.54 (8H, m), 7.83-7.86 (2H,app-d, J=7.9 Hz), 8.35-8.37 (1H, m), 8.49-8.52 (1H, dd, J=1.3 Hz, 7.3Hz), approximately 12.8 (1H, br), approximately 14.2 (1H, br)

Example 403-(3-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(53 mg, 0.14 mmol, prepared in Example 20) in acetic acid (2 ml) wasadded 47% hydrogen bromide (1.5 ml), and the mixture was heated underreflux overnight. The reaction mixture was admixed with water, andfiltered to give precipitates which were dried to afford3-(3-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(39 mg, 76%).

mp 276-278° C.

¹H NMR (DMSO-d₆) δ:4.26 (2H, s), 6.54-6.58 (1H, m), 6.72-6.77 (2H, m),7.02-7.08 (1H, app-t, J=7.9 Hz), 7.25-7.28 (2H, m), 7.30-7.35 (1H,app-dd, J=4.6 Hz, 7.9 Hz), 7.41-7.55 (3H, m), 8.34-8.37 (1H, app-dd,J=1.7 Hz, 4.6 Hz), 8.48-8.52 (1H, app-dd, 1.6 Hz, 7.9 Hz), 9.29 (1H, s)

Example 413-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(100 mg, 0.26 mmol, prepared in Example 21) in acetic acid (1 ml) wasadded 47% hydrogen bromide (44 μl), and the mixture was heated underreflux. After additional 47% hydrogen bromide (144 μl) was added, themixture was heated under reflux overnight. The reaction mixture wasadmixed with water, and filtered to give precipitates which were driedto afford3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(92.1 mg, 96%).

mp 316-317° C.

¹H NMR (DMSO-d₆) δ: 4.23 (2H, s), 6.63-6.67 (2H, app-d, J=8.6 Hz),7.11-7.14 (2H, app-d, J=8.6 Hz), 7.25-7.34 (3H, m), 7.44-7.55 (3H, m),8.34-8.36 (1H, m), 8.47-8.51 (1H, app-dd, J=2.0 Hz, 7.6 Hz), 9.22 (1H,s), 14.2 (1H, s)

Example 423-(2-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(50 mg, 0.13 mmol, prepared in Example 22) in acetic acid (1 ml) wasadded 47% hydrogen bromide (0.5 ml), and the mixture was heated underreflux. After additional 47% hydrogen bromide (1 ml) and acetic acid (1ml) was added, the mixture was heated under reflux for 2 days, thenadmixed with water, filtered to give precipitates which were dried toafford3-(2-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one(31 mg, 64%).

mp 278-280° C.

¹H NMR (DMSO-d₆) δ:4.30 (2H, s), 6.65-6.70 (1H, app-t, J=7.9 Hz),6.79-6.82 (1H, app-d, J=8.3 Hz), 6.94-7.05 (2H, m), 7.24-7.27 (2H,app-d, J=8.1 Hz), 7.30-7.35 (1H, m), 7.40-7.54 (3H, m), 8.34-8.36 (1H,m), 8.50-8.52 (1H, m)

Example 433-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(200 mg, 0.50 mmol, prepared in Example 24) in DMF (10 ml) and methanol(10 ml) was added activated carbon-palladium (20 mg), the mixture wasstirred under hydrogen atmosphere for 3 days, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(120 mg, 65%).

mp 210-212° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.16 (2H, s), 4.89 (2H, brs), 6.44-6.47 (2H, app-d,J=8.2 Hz), 6.97-7.00 (2H, app-d, J=8.6 Hz), 7.23-7.33 (3H, m), 7.40-7.55(3H, m), 8.32-8.35 (1H, dd, J=1.7 Hz, 4.6 Hz), 8.46-8.50 (1H, dd, J=1.6Hz, 7.6 Hz), approximately 14 (1H, br)

Example 443-(3-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(273 mg, 0.69 mmol, prepared in Example 25) in DMF (14 ml) and methanol(14 ml) was added activated carbon-palladium (27 mg), the mixture wasstirred under hydrogen atmosphere overnight, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-(3-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(220 mg, 87%).

mp 286.5-288.5° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.20 (2H, s), 4.98 (2H, s), 6.35-6.38 (1H, d, J=8.6Hz), 6.46-6.49 (2H, m), 6.86-6.92 (1H, t, J=7.9 Hz), 7.25-7.28 (2H, d,J=7.6 Hz), 7.29-7.34 (1H, dd, J=4.9 Hz, 7.6 Hz), 7.41-7.54 (3H, m),8.34-8.35 (1H, d, J=3.3 Hz), 8.48-8.51 (1H, dd, J=1.3 Hz, 7.6 Hz),approximately 14 (1H, brs)

Example 453-(2-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(376 mg, 0.95 mmol, prepared in Example 26) in DMF (20 ml) and methanol(20 ml) was added activated carbon-palladium (38 mg), the mixture wasstirred under hydrogen atmosphere overnight, and filtered. Aftermethanol was distilled off, the resultant solution was admixed withwater, and filtered to give precipitates which were dried to afford3-(2-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(349 mg, 100%).

mp>320° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.17 (2H, s), 5.19 (2H, brs), 6.45-6.51 (1H, td,J=7.6 Hz, 1.3 Hz), 6.57-6.61 (1H, dd, J=1.0 Hz, 7.9 Hz), 6.87-6.93 (1H,td, J=7.6 Hz, 1.3 Hz), 7.04-7.08 (1H, dd, J=1.3 Hz, 7.6 Hz), 7.24-7.28(2H, m), 7.31-7.36 (1H, dd, J=4.6 Hz, 7.6 Hz), 7.41-7.56 (3H, m),8.35-8.38 (1H, dd, J=1.7 Hz, 4.6 Hz), 8.49-8.53 (1H, dd, J=1.7 Hz, 7.6Hz), approximately 14 (1H, brs)

Example 463-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

3-(4-Ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(110 mg, 0.25 mmol, prepared in Example 32) was dissolved in DMSO (3 ml)at 50° C., admixed with 50% sulfuric acid (2 ml) at 100° C., and thenheated under reflux for 1 hour. The reaction mixture was admixed withwater, and filtered to give precipitates which were dried to afford3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(96 mg, 93%).

mp 297-300° C.

¹H NMR (DMSO-d₆) δ:3.49 (2H, s), 4.33 (2H, brs), 7.14-7.34 (7H, m),7.40-7.55 (3H, m), 8.36 (1H, br), 8.47-8.51 (1H, dd, J=1.7 Hz, 7.6 Hz),approximately 12.3 (1H, br), 14.11 (1H, br)

Example 473-(4-acetoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(192 mg, 0.52 mmol, prepared in Example 41) in DMF (2 ml) was added asolution of 1-acetylimidazole (114 mg, 1.04 mmol, 2 eq.) in DMF (2 ml)while ice-cooling, and the mixture was stirred overnight at roomtemperature, and then diluted with aqueous sodium hydrogen carbonate.Precipitates were filtered off, and the mixture was dried and purifiedby flash column chromatography to afford3-(4-acetoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(128 mg, 60%).

mp 278-282° C.

¹H NMR (DMSO-d₆) δ:2.23 (3H, s), 4.36 (2H, s), 7.01-7.04 (2H, app-d,J=8.3 Hz), 7.26-7.54 (8H, m), 8.36-8.52 (2H, m), 14.16 (1H, s)

Example 483-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(38 mg, 0.10 mmol, prepared in Example 13) in pyridine (2 ml) was addedmethanesulfonyl chloride (18.5 mg, 0.16 mmol, 1.6 eq.), and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasadmixed with water, and filtered to give precipitates which were driedto afford3-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(43 mg, 86%).

mp 284-285° C.

¹H NMR (DMSO-d₆) δ:2.96 (3H, s), 3.18-3.26 (4H, m), 7.15-7.53 (10H, m),8.34-8.51 (2H, m), 8.82 (1H, s), 13.80 (1H, s)

Example 493-(4-methanesulfonylaminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a solution of3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(107 mg, 0.29 mmol, prepared in Example 43) in pyridine (2 ml) was addedmethanesulfonyl chloride (47 mg, 0.41 mmol, 1.4 eq.), and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasadmixed with water, and filtered to give precipitates which were driedand purified by flash column chromatography to afford3-(4-methanesulfonylamino-benzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(84 mg, 65%).

mp 306-307° C.

¹H NMR (DMSO-d₆) δ:2.93 (3H, s), 4.31 (2H, s), 7.09-7.12 (2H, app-d,J=8.3 Hz), 7.26-2.31 (5H, m), 7.44-7.54 (3H, m), 8.35-8.36 (1H, m),8.48-8.51 (1H, app-dd, 2.0 Hz, 7.9 Hz), 9.60 (1H, s), 14.20 (1H, s)

Example 505-phenyl-3-[2-(2-ureidophenyl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one

To a suspension of3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(38 mg, 0.09 mmol, prepared in Example 36) in a mixture solvent ofacetic acid (1 mL) and water (1 mL) was added potassium cyanate (12 mg,0.15 mmol, 1.7 eq) at room temperature. The mixture was stirredovernight at 35° C., and filtered to give precipitates which were washedwith water and then dried to afford5-phenyl-3-[2-(2-ureidophenyl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(40 mg, 94%).

mp 300-305° C.

¹H NMR (DMSO-d₆) δ:2.91-2.98 (2H, m), 3.10-3.14 (2H, m), 5.80 (2H, s),6.87-6.92 (1H, m), 7.09-7.14 (1H, m), 7.16-7.19 (1H, m), 7.32-7.35 (2H,m), 7.38-7.42 (1H, app-dd, J=4.6 Hz, 7.3 Hz), 7.46-7.57 (3H, m),7.93-7.96 (1H, app-d, J=8.3 Hz), 8.23 (1H, s), 8.42-8.43 (1H, m),8.54-8.57 (1H, app-dd, 1.7 Hz, 7.9 Hz)

Example 513-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

A suspension of 4-hydroxy-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one(1.07 g, 4.0 mmol; prepared according to JP, A, 61-246183 (1986) and/orJ. Med. Chem., 31, 2108 (1988)) in DMF (4 ml) was added sodium hydride(about 60%, 352 mg, 8.8 mmol, 2.2 eq.), and the mixture was stirreduntil the production of hydrogen was completed. Next, after phenylacetylchloride (0.63 ml, 4.8 mmol, 1.2 eq.) was added, the mixture was stirredat room temperature, admixed with water, acidified with hydrochloricacid, and then filtered off to give precipitates which were washed withwater. The resulting precipitate was suspended in DMF (8 mL) withoutpurification, treated with hydrazine monohydrate (80%, 513 μl, 12.8mmol, 3.2 eq.), and the mixture was stirred at 100 to 110° C. for 2hours. The reaction mixture was admixed with water, and filtered off togive precipitates which were dried to afford3-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(826 mg, 54%).

mp>320° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:3.83 (3H, s), 4.35 (2H, s), 7.01-7.07 (2H, app-d,J=9.1 Hz), 7.13-7.18 (2H, app-d, J=8.9 Hz), 7.19-7.35 (6H, m), 8.35 (1H,dd, J=1.8 Hz, 4.8 Hz), 8.48 (1H, dd, J=1.8 Hz, 7.7 Hz), 14.07 (1H, br)

Example 523-benzyl-5-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(200 mg, 0.52 mmol, prepared in Example 51) in acetic acid (2 ml) wasadded 47% hydrogen bromide (1 ml), and the mixture was heated underreflux overnight. The reaction mixture was admixed with water, andfiltered to give precipitates which were dried to afford3-benzyl-5-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(165 mg, 86%).

mp>320° C.

¹H NMR (DMSO-d₆) δ:4.35 (2H, s), 6.84-6.87 (2H, app-d, J=8.6 Hz),6.99-7.02 (2H, app-d, J=8.6 Hz), 7.15-7.35 (6H, m), 8.35-8.37 (1H, m),8.47 (1H, dd, J=1.8 Hz, 7.7 Hz), 9.57 (1H, brs), 14.08 (1H, br)

Example 533-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2(1H)-one(314 mg, 0.82 mmol, prepared in Synthetic Example 29) in DMF (4 ml) wasadded hydrazine monohydrate (80%, 132 μl, 4.12 mmol, 4.0 eq.), and themixture was stirred at 100 to 110° C. for 2 hours. The reaction mixturewas admixed with water, and filtered to give precipitates which werewashed with water and dried to afford3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(287 mg, 92%).

mp 285-287° C. (dec.)/DMF-H₂O

¹H NMR (DMSO-d₆) δ:4.36 (2H, s), 7.15-7.38 (6H, m), 7.71 (1H, dt, J=8.2Hz, 1.8 Hz), 7.34 (1H, t, J=8.1 Hz), 7.91-7.95 (2H, m), 8.36 (1H, dd,J=1.6 Hz, 4.8 Hz), 8.51 (1H, dd, J=1.6 Hz, 7.7 Hz)

Example 543-benzyl-5-(3-carboxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(120 mg, 0.32 mmol, prepared in Example 53) in DMSO (15 ml) was added50% sulfuric acid (5 ml), and the mixture was heated under reflux for2.5 hours. The reaction mixture was admixed with water, and filtered togive precipitates which were dried to afford3-benzyl-5-(3-carboxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(73 mg, 58%).

mp 300-305° C.

¹H NMR (DMSO-d₆) δ:4.32-4.39 (2H, m), 7.20-7.35 (6H, m), 7.55 (1H, dt,J=8.4 Hz, 1.8 Hz), 7.65 (1H, t, J=7.7 Hz), 7.80 (1H, t, J=1.6 Hz), 8.02(1H, dt, J=7.7 Hz, 1.5 Hz), 8.35 (1H, br), 8.51 (1H, d, J=6.3 Hz), 13.05(1H, br), 14.15 (1H, br)

Example 555-phenyl-3-(3-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-3-(1-oxo-4-phenylbutyl)-1-phenyl-1,8-naphthyridin-2(1H)-one(384 mg, 1.0 mmol, prepared in Synthetic Example 30) in DMF (4 ml) wasadded hydrazine monohydrate (80%, 160 μl, 4.0 mmol, 4.0 eq.), and themixture was stirred at 100 to 110° C. for 2 hours. The reaction mixturewas admixed with water, and filtered to give precipitates which werewashed with water and dried to afford5-phenyl-3-(3-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(354 mg, 93%).

mp 202-203.5° C./DMF-H₂O

¹H NMR (DMSO-d₆) δ:2.04 (2H, app-quin., J=7.6 Hz), 2.65 (2H, t, J=7.6Hz), 3.01 (2H, t, J=7.9 Hz), 7.12-7.30 (7H, m), 7.31 (1H, dd, J=4.6 Hz,7.6 Hz), 7.40-7.54 (3H, m), 8.34 (1H, dd, J=2.0 Hz, 4.9 Hz), 8.48 (1H,dd, J=2.0 Hz, 7.6 Hz), approximately 14 (1H, br)

Example 563-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one (1.13 g, 4 mmol,obtained in Synthetic Example 4 (3)) in DMF (16 ml) was added sodiumhydride (about 60%, 384 mg, 9.6 mmol, 2.4 eq.), and the mixture wasstirred until the production of hydrogen was completed. Next, afterphenylacetyl chloride (742 mg, 4.8 mmol, 1.2 eq.) was added, the mixturewas stirred at room temperature, followed by addition of water. Afteracidified with hydrochloric acid, it was filtered to give precipitateswhich were washed with water and suspended in DMF (16 mL) withoutfurther purification. To the suspension was added hydrazine monohydrate(80%, 448 μl, 11.2 mmol, 2.8 eq.), and the resultant mixture was stirredat 100 to 110° C. overnight. The reaction mixture was admixed withwater, and filtered to give precipitates which were dried to afford3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(714 mg, 45%).

mp 276-279° C./DMF-H₂O

¹H NMR (DMSO-d₆, measuring temperature: 80° C.) δ:4.37 (2H, s),7.16-7.34 (6H, m), 7.73-7.83 (2H, m), 8.19-8.36 (3H, m), 8.45-8.52 (1H,m), 13.95 (1H, m)

Example 575-(3-aminophenyl)-3-benzyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a solution of3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(98 mg, 0.25 mmol) in conc. hydrochloric acid (7 ml) was added tinchloride.2H₂O (500 mg, 5-fold weights), and the mixture was stirred atroom temperature for 1.5 hour, admixed with water, then treated withsodium carbonate to make it to pH8-9, and extracted with chloroform 8times. The organic layer was dried over anhydrous magnesium sulfate, andevaporated to give5-(3-aminophenyl)-3-benzyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(63 mg, 70%).

mp 277-279° C.

¹H NMR (DMSO-d₆) δ:4.34 (2H, s), 5.16 (2H, s), 6.32-6.37 (2H, m),6.59-6.61 (1H, m), 7.08-7.34 (7H, m), 8.36-8.38 (1H, app-dd, J=2.0 Hz,4.9 Hz), 8.44-8.48 (1H, app-dd, 2.0 Hz, 7.9 Hz), 14.09 (1H, brs)

Example 583-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one

To a suspension of1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one (512 mg, 2.0mmol, obtained in Synthetic Example 31 (3)) in DMF (8 ml) was addedsodium hydride (about 60%, 192 mg, 4.8 mmol, 2.4 eq.), the mixture wasstirred until the production of hydrogen was completed.

Next, after phenylacetyl chloride (371 mg, 2.4 mmol, 1.2 eq.) was added,the mixture was stirred at room temperature, and treated with water. Theresultant DMF layer was washed with hexane, acidified with hydrochloricacid, and filtered to give precipitates which were washed with water,and then suspended in DMF (8 mL). To the suspension was added hydrazinemonohydrate (80%, 224 μl, 5.6 mmol, 2.8 eq.), and the mixture wasstirred overnight at 100 to 110° C. The reaction mixture was admixedwith water, and filtered to give precipitates which were washed withwater, then dissolved in DMF, and treated with methanol and water. Themixture was filtered to give precipitates which were washed with waterand dried to afford3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one(330 mg, 45%).

mp 298-299° C./DMF-MeOH—H₂O

¹H NMR (DMSO-d₆) δ: 4.35 (2H, s), 7.13-7.36 (9H, m), 7.50-7.59 (1H, m),8.35-8.38 (1H, app-dd, J=2.0 Hz, 4.9 Hz), 8.48-8.51 (1H, app-dd, J=2.0Hz, 7.9 Hz), 14.14 (1H, brs)

Formulation Examples Formulation Example 1

A formula for one tablet (total amount per tablet: 150 ma) is givenbelow:

Compound of the present invention 30 mg Crystalline Cellulose 90 mg CornStarch 28 mg Magnesium Stearate  2 mg

The ingredients were formulated into tablets by known methods accordingto general pharmaceutical rules prescribed in JPXIV.

Formulation Example 2

A formula for one capsule (total amount per capsule: 180 mg) is givenbelow:

Compound of the present invention 50 mg Lactose 100 mg  Corn Starch 28mg Magnesium Stearate  2 mg

The ingredients were formulated into capsules by known methods accordingto general pharmaceutical rules prescribed in JPXIV.

Formulation Example 3

The compound of the present invention (10 mg) was dissolved in 3 ml ofphysiological saline. The solution was adjusted to pH 7 with 0.1 Naqueous sodium hydroxide, to which was added physiological saline tomake the total volume 5 ml. The resulting solution was dispensed to eachampule, and then subjected to heat sterilization to obtain injections.

Formulation Example 4

To a mixture of the compound of the present invention (1 g), egg yolklecithin (1.2 g), α-tocopherol (20 mg) and ascorbic acid (33 mg) wasadded purified water to make the total volume 100 ml. The resultingproduct was used as a pharmaceutical preparation for aerosols.

INDUSTRIAL APPLICABILITY

The present invention relates to PDE IV inhibitors. The compounds of thepresent invention possess potent inhibiting properties toward PDE IV.The compounds inhibit PDE IV predominantly present in bronchial smoothmuscle cells and inflammatory cells, thereby leading to an elevation ofcAMP levels in such cells, with the result that it may be expected toachieve relaxation of bronchial smooth muscle and suppression ofinflammatory cell activation. Since it is noted that the compounds havea great difference between their pharmacologically-effective dose leveland their inhibitory dose level for drug-metabolizing enzymes, ascompared with the prior art PDE IV inhibitors. The present inventionenables the production of safer anti-asthmatics, prophylactic and/ortherapeutic drugs for COPD, and others, which possess excellentpharmacological properties.

While specific details of the present invention have been described interms of preferred embodiments and examples, it will be apparent tothose of skill in the art that variations may be applied to thosedisclosed in the foregoing. In light of the disclosure, variousmodifications and rearrangements which can be made to those set forthherein are deemed to be within the spirit and scope of the appendedclaims.

1-9. (canceled)
 10. A compound of the formula (1):

wherein: A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may beunsubstituted or optionally substituted with one or more membersselected from the group consisting of hydroxyl, halogen, cyano, nitro,lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl,lower alkoxycarbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-loweralkylene, lower alkylsulfonyl, lower alkylsulfonylamino, and ureido; R¹is a group selected from the group consisting of hydrogen, hydroxyl,halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and loweralkoxycarbonyl; R² is hydrogen or lower alkyl; and m is an integer of 1to 3; with the proviso that3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one and3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-oneare excluded from said compound; or a pharmaceutically acceptable saltthereof.
 11. The compound according to claim 10, wherein A is phenyl; ora pharmaceutically acceptable salt thereof.
 12. The compound accordingto claim 10, wherein A is pyridyl or 1-oxypyridyl; or a pharmaceuticallyacceptable salt thereof.
 13. A compound, or a pharmaceuticallyacceptable salt thereof, which is selected from the group consisting of5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-oneand3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one.14. A pharmaceutical composition which comprises an effective amount ofa compound according to claim 10, or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutically acceptable carrier.
 15. Amethod of inhibiting a phosphodiesterase IV comprising contacting aneffective amount of a compound according to claim 10, or apharmaceutically acceptable salt thereof, with a phosphodiesterase IV.16. A method for treating a mammal with at least one respiratory diseaseselected from the group consisting of: bronchial asthma includingchronic bronchial asthma and atopic asthma; acute bronchitis; chronicbronchitis; asthmatic bronchitis; pneumonic diseases; pulmonaryemphysema; chronic obstructive pulmonary disease (COPD); and acuterespiratory distress syndrome (ARDS) comprising administering aneffective amount of a compound according to claim 10, or apharmaceutically acceptable salt thereof, to said mammal.
 17. A methodfor treating a mammal with asthma comprising administering an effectiveamount of a compound according to claim 10, or a pharmaceuticallyacceptable salt thereof, to said mammal.
 18. A pharmaceuticalcomposition which comprises an effective amount of a compound accordingto claim 11, or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition which comprises an effective amount of a compound accordingto claim 12, or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable carrier.
 20. A pharmaceuticalcomposition which comprises an effective amount of a compound accordingto claim 13, or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable carrier.
 21. A method of inhibiting aphosphodiesterase IV comprising contacting an effective amount of acompound according to claim 11, or a pharmaceutically acceptable saltthereof, with a phosphodiesterase IV.
 22. A method of inhibiting aphosphodiesterase IV comprising contacting an effective amount of acompound according to claim 12, or a pharmaceutically acceptable saltthereof, with a phosphodiesterase IV.
 23. A method of inhibiting aphosphodiesterase IV comprising contacting an effective amount of acompound according to claim 13, or a pharmaceutically acceptable saltthereof, with a phosphodiesterase IV.
 24. A method for treating a mammalwith at least one respiratory disease selected from the group consistingof: bronchial asthma including chronic bronchial asthma and atopicasthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis;pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonarydisease (COPD); and acute respiratory distress syndrome (ARDS) saidmethod comprising administering an effective amount of a compoundaccording to claim 11, or a pharmaceutically acceptable salt thereof, tosaid mammal.
 25. A method for treating a mammal with at least onerespiratory disease selected from the group consisting of: bronchialasthma including chronic bronchial asthma and atopic asthma; acutebronchitis; chronic bronchitis; asthmatic bronchitis; pneumonicdiseases; pulmonary emphysema; chronic obstructive pulmonary disease(COPD); and acute respiratory distress syndrome (ARDS) said methodcomprising administering an effective amount of a compound according toclaim 12, or a pharmaceutically acceptable salt thereof, to said mammal.26. A method for treating a mammal with at least one respiratory diseaseselected from the group consisting of: bronchial asthma includingchronic bronchial asthma and atopic asthma; acute bronchitis; chronicbronchitis; asthmatic bronchitis; pneumonic diseases; pulmonaryemphysema; chronic obstructive pulmonary disease (COPD); and acuterespiratory distress syndrome (ARDS) said method comprisingadministering an effective amount of a compound according to claim 13,or a pharmaceutically acceptable salt thereof, to said mammal.
 27. Amethod for treating a mammal with asthma comprising administering aneffective amount of a compound according to claim 11, or apharmaceutically acceptable salt thereof, to said mammal.
 28. A methodfor treating a mammal with asthma comprising administering an effectiveamount of a compound according to claim 12, or a pharmaceuticallyacceptable salt thereof, to said mammal.
 29. A method for treating amammal with asthma comprising administering an effective amount of acompound according to claim 13, or a pharmaceutically acceptable saltthereof, to said mammal.